Compounds for treatment of cancer

ABSTRACT

The present invention relates to a compound of formula XXII and a compound of formula 17ya, which are defined as anywhere in the specification, to a composition comprising the same, and to a method of using thereof in the treatment of various forms of cancer.

CROSS-REFERENCE TO RELATED APPLICATIONS

This Application is a Continuation of application of U.S. applicationSer. No. 14/692,597 filed on Apr. 21, 2015 which is a ContinuationApplication of U.S. application Ser. No. 14/049,950 filed on Oct. 9,2013 which is a Continuation-in-Part application of U.S. applicationSer. No. 12/485,881 filed on Jun. 16, 2009, which claims the benefit ofU.S. Provisional Patent Application Ser. No. 61/061,875, filed on Jun.16, 2008, all of which are incorporated herein by reference in theirentirety.

This Application is a Continuation-in-Part application of U.S.application Ser. No. 13/676,650, filed on Nov. 14, 2012, which is acontinuation-in-part application of U.S. application Ser. No.13/216,927, filed on Aug. 24, 2011, which is a continuation-in-partapplication of U.S. application Ser. No. 12/981,233, filed on Dec. 29,2010, which claims the benefit of U.S. Provisional Application Ser. No.61/376,675, filed on Aug. 24, 2010; U.S. Provisional Application Ser.No. 61/315,790, filed on Mar. 19, 2010; and U.S. Provisional ApplicationSer. No. 61/309,360, filed on Mar. 1, 2010, all of which areincorporated herein by reference in their entirety.

GOVERNMENT INTEREST STATEMENT

This invention was made in whole or in part with government supportunder Grant Number 1R15CA125623-01A2 and 1R01CA148706-01A1, awarded bythe NIH (National Institutes of Health). This invention was also madewith funding received from the U.S. Department of Defense under grantDAMD 17-01-1-0830 and the National Institutes of Health under Core Grant21765. The U.S. government has certain rights in this invention.

FIELD OF THE INVENTION

The present invention relates to novel compounds having anti-canceractivity, compositions comprising the same, and their use for treatingvarious forms of cancer.

BACKGROUND OF THE INVENTION

Cancer is the second most common cause of death in the United States,exceeded only by heart disease. In the United States, cancer accountsfor 1 of every 4 deaths. The 5-year relative survival rate for allcancers patients diagnosed in 1996-2003 is 66%, up from 50% in 1975-1977(Cancer Facts & Figures American Cancer Society: Atlanta, Ga. (2008)).This improvement in survival reflects progress in diagnosing at anearlier stage and improvements in treatment. Discovering highlyeffective anticancer agents with low toxicity is a primary goal ofcancer research.

2-Aryl-thiazolidine-4-carboxylic acid amides (ATCAA) have been describedas potent cytotoxic agents for both prostate cancer and melanoma (Li etal., “Synthesis and Antiproliferative Activity of Thiazolidine Analogsfor Melanoma,” Bioorg. Med. Chem. Lett. 17:4113-7 (2007); Li et al.,“Structure-Activity Relationship Studies of Arylthiazolidine Amides asSelective Cytotoxic Agents for Melanoma,” Anticancer Res. 27:883-888(2007); Lu et al., “Synthesis and Biological Evaluation of2-Arylthiazolidine-4-Carboxylic Acid Amides for Melanoma and ProstateCancer,” Abstracts of Papers, 234th ACS National Meeting, Boston, Mass.,United States, Aug. 19-23, 2007, MEDI-304; Gududuru et al., “SAR Studiesof 2-Arylthiazolidine-4-Carboxylic Acid Amides: A Novel Class ofCytotoxic Agents for Prostate Cancer,” Bioorg. Med Chem. Lett.15:4010-4013 (2005); Gududuru et al., “Discovery of2-Arylthiazolidine-4-Carboxylic Acid Amides as a New Class of CytotoxicAgents for Prostate Cancer,” J. Med Chem. 48:2584-2588 (2005)). These2-aryl-thiazolidine-4-carboxylic acid amides were designed from thelysophosphatidic acid (LPA) structure with a lipid chain. This designchoice was directed toward inhibition of GPCR (guanine-bindingprotein-coupled receptor) signaling, which is involved in proliferationand survival of prostate cancer (Raj et al., “Guanosine PhosphateBinding Protein Coupled Receptors in Prostate Cancer: A Review,” J.Urol. 167:1458-1463 (2002); Kue et al., “Essential Role for G Proteinsin Prostate Cancer Cell Growth and Signaling,” J. Urol. 164:2162-7(2000); Guo et al., “Expression and Function of Lysophosphatidic AcidLPA1 Receptor in Prostate Cancer Cells,” Endocrinology 147:4883-4892(2006); Qi et al., “Lysophosphatidic Acid Stimulates Phospholipase DActivity and Cell Proliferation in PC-3 Human Prostate Cancer Cells,” J.Cell. Physiol. 174:261-272 (1998)).

The most potent of the 2-aryl-thiazolidine-4-carboxylic acid amidescould inhibit prostate cancer cells with an average IC₅₀ in the rangefrom 0.7 to 1.0 μM and average IC₅₀ values against melanoma cells were1.8˜2.6 μM (Li et al., “Synthesis and Antiproliferative Activity ofThiazolidine Analogs for Melanoma,” Bioorg. Med. Chem. Lett. 17:4113-7(2007)). One preferred compound, (2RS,4R)-2-phenyl-thiazolidine-4-carboxylic acid hexadecylamide, was sent tothe United States National Cancer Institute 60 human tumor cell lineanticancer drug screen (NCI-60). Results from NCI-60 assay showed thatthis compound could inhibit growth of all nine types of cancer cellswith IC₅₀ values in the range from 0.124 μM (Leukemia, CCRF-CEM) to 3.81μM (Non-Small Cell Lung Cancer, NCI-H522). Further improvement inanti-cancer activity of these compounds, in terms of their IC₅₀ values,would be desirable.

The present invention is directed to overcoming these and otherdeficiencies in the prior art.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides a compound represented byformula XXII:

-   -   wherein    -   A is indolyl;    -   wherein said A is optionally substituted by substituted or        unsubstituted O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl,        CF₃, CN, —CH₂CN, NH₂, hydroxyl, —(CH₂)_(i)NHCH₃, —(CH₂)_(i)NH₂,        —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃, substituted or unsubstituted        —SO₂-aryl, substituted or unsubstituted C₁-C₅ linear or branched        alkyl, substituted or unsubstituted haloalkyl, substituted or        unsubstituted alkylamino, substituted or unsubstituted        aminoalkyl, —OCH₂Ph, substituted or unsubstituted —NHCO-alkyl,        COOH, substituted or unsubstituted —C(O)Ph, substituted or        unsubstituted C(O)O-alkyl, C(O)H, —C(O)NH₂, NO₂ or combination        thereof; and    -   i is an integer between 0-5;    -   R₁ is hydrogen, linear or branched, substituted or unsubstituted        alkyl, substituted or unsubstituted aryl, —CH₂Ph, substituted        benzyl, haloalkyl, aminoalkyl, —OCH₂Ph, substituted or        unsubstituted SO₂-aryl, substituted or unsubstituted —(C═O)-aryl        or OH; or an N-oxide thereof, or a pharmaceutically acceptable        salt thereof.

In another aspect, the present invention provides a compound representedby formula 17ya:

or an N-oxide or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides a compound representedby formula 17yab or 17yac:

In another aspect, the present invention provides a pharmaceuticalcomposition comprising a compound of formula XXII or 17ya, or an N-oxidethereof, or a pharmaceutically acceptable salt thereof, and at least onepharmaceutically acceptable carrier. In some embodiments, thepharmaceutical composition of the present invention is useful for thetreatment of cancer.

In yet another aspect, the present invention provides a method oftreating, suppressing, reducing the severity, reducing the risk, orinhibiting cancer comprising administering a compound of formula XXII or17ya to a subject having cancer under conditions effective to treat thecancer. In some embodiments, said cancer is selected from the groupconsisting of prostate cancer, drug-resistant prostate cancer, breastcancer, ovarian cancer, drug-resistant ovarian cancer, skin cancer,melanoma, lung cancer, colon cancer, glioma, leukemia, renal cancer, CNScancer, uterine cancer, drug-resistant uterine cancer, and combinationsthereof. In some embodiments, said cancer is melanoma cancer. In certainembodiments, said cancer is metastatic melanoma. In other embodiments,said cancer is prostate cancer. In some embodiments, said cancer isovarian cancer. In some embodiments, said administering is carried outin combination with another cancer therapy.

In yet another aspect, the present invention provides a method oftreating a drug resistant tumor or tumors comprising administering acompound of formula XXII or 17ya to a subject suffering from cancerunder conditions effective to treat the drug resistant tumor or tumors.In some embodiments, said cancer is melanoma cancer. In certainembodiments, said cancer is metastatic melanoma. In other embodiments,said cancer is prostate cancer. In some embodiments, said cancer isovarian cancer. In some embodiments, said cancer is uterine cancer. Insome embodiments, said administering is carried out in combination withanother cancer therapy.

In yet another aspect, the present invention provides a method ofdestroying a cancerous cell comprising providing a compound of formulaXXII or 17ya and contacting the cancerous cell with the compound underconditions effective to kill the cancer cell.

In one embodiment, the present invention provides a method ofinhibiting, preventing, or slowing the progress of vascularization of atumor comprising administering a compound of this invention to a subjecthaving cancer under conditions effective to inhibit, prevent or slow theprogress of vascularization of the tumor.

Other features and advantages of the present invention will becomeapparent from the following detailed description, examples, and figures.It should be understood, however, that the detailed description and thespecific examples while indicating preferred embodiments of theinvention are given by way of illustration only, since various changesand modifications within the spirit and scope of the invention willbecome apparent to those skilled in the art from this detaileddescription.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an Oak Ridge Thermal Ellipsoid Plot (ORTEP) drawing ofcompound 8f with thermal ellipsoids depicted at 50% probability level.The drawing was generated following X-ray crystallography studies.

FIG. 2 illustrates NMR studies measuring the auto-dehydrogenation fromthiazoline to thiazole compound 8f. At 0 day, NMR sample containedthiazoline and thiazole mixtures in CDCl₃; ratio is about 3:2. At 9^(th)day, thiazoline compound was nearly completely converted to thiazolecompound 8f.

FIGS. 3A and 3B illustrate the effect of compound 8f on cell cycledistribution of LNCaP prostate cancer cells. FIG. 3A illustrates theeffect of various dosages (10 nM, 50 nM, 200 nM, and 500 nM) of compound8f relative to control. Amounts in excess of the IC₅₀ value illustrate asignificant change in cell cycle distribution. FIG. 3B graphicallyillustrates the change in G2/M versus G1 cell cycle distribution.

FIG. 4 is a graph illustrating the effect of compound 8f on tubulinassembly.

FIGS. 5A and 5B are graphs illustrating the ability of compounds 8f and8n to significantly inhibit A375 melanoma colony formation in an invitro assay. At 0.3 μM or above, colony formation is completelyinhibited.

FIG. 6 is a graph illustrating the ability of compound 8n (6 mg/kg, IPdaily injection) to inhibit B16 melanoma tumor growth in vivo.

FIG. 7 depicts the synthetic scheme of compounds of this invention.Reagents and conditions: (a) L-cysteine, EtOH, 65° C.; (b) EDCI, HOBt,NMM, HNCH₃OCH₃, CH₂Cl₂; (c) TBDMSCl, imidazole, THF; (d)3,4,5-trimethoxyphenylbromide, BuLi, THF; (e) TBAF, THF; (f) SOCl₂,Et₂O; (g) NH₃, MeOH; (h) POCl₃; (i) PhSO₂Cl, Bu₄NHSO₄, toluene, 50%NaOH; (j) 1 N NaOH, EtOH, reflux; (k) Boc₂O, 1 N NaOH, 1,4-dioxane; (l)CBrCl₃, DBU, CH₂Cl₂; (m) 4 N HCl in 1,4-dioxane; (n) NaH, DMF, Mel; (o)HCHO, NaBH₃CN, Et₃N.

FIG. 8 depicts the synthetic scheme of compound 15xaa and 12xa. Reagentsand conditions: (a) 1. KOH, ethanol; 2. PhSO₂Cl, acetone, RT; (b) NH₄OH,glyoxal, ethanol, RT; (c) NaH, PhSO₂Cl, THF, 0° C.—RT; (d) t-BuLi (1.7Min pentane), 3,4,5-trimethoxybenzoyl chloride, THF, −78° C.; (e) NaOH,ethanol, H₂O, reflux.

FIG. 9 depicts synthetic scheme of 17ya, 17yab and 17yac. Reagents andconditions: (a) 1. KOH, ethanol, 2. PhSO₂Cl, acetone, RT; (b) NH₄OH,glyoxal, ethanol, RT; (c) NaH, PhSO₂Cl, THF, 0° C.—RT; (d) t-BuLi (1.7 Min pentane), 3,4,5-trimethoxybenzoyl chloride, THF, −78° C.; (e) NaOH,ethanol, H₂O, reflux; (f) TBAF, THF, RT; (g) NaH, CH₃I, THF.

FIGS. 10A-10D depicts the effect of 17ya and 55 on tubulinpolymerization. Compounds 17ya and 55 bind to colchicine-binding site ontubulin, and inhibit tubulin polymerization. FIG. 10A, competitive massbinding. Tubulin (1 mg/mL) and colchicine (1.2 μM) were incubated withvarious concentrations of podophylltoxin, vinblastine, compounds 17ya,and 55. N=3; mean±SD. Podophylltoxin and vinblastine were used aspositive and negative controls, respectively. FIG. 10B, effect ontubulin polymerization. Tubulin (0.4 mg) was exposed to test compounds(5 μM). Colchicine was used as positive control. FIGS. 10C and 10D,ability of 17ya and 55 to enhance cytoplasmic DNA-Histone complexformation (apoptosis) at 24 h in PC-3 (Figure C) and PC-3/TxR (Figure D)cells (N=3); mean±SD. Docetaxel was used as positive control.

FIGS. 11A to 11D depicts in vivo anticancer efficacy. FIG. 11A, Nudemice bearing PC-3 tumors were treated with docetaxel (i.v., 10 or 20mg/kg) on day 1 and 9. (N=5-6). Bars, SE. FIG. 11B, Nude mice bearingPC-3/TxR tumors were treated with docetaxel (i.v., 10 or 20 mg/kg) onday 1 and 9, or compound 17ya treatments (p.o., 6.7 mg/kg) once daily,five days a week. (N=4-5). Bars, SE. FIG. 11C, Nude mice bearingPC-3/TxR tumors were treated with compound 17ya (PO, 3.3 mg/kg) twice aday for four days in the first week, and then dosed once a day, fivedays a week for weeks 2-4 (N=7), or with compound 55 treatments (p.o.,10 or 30 mg/kg) twice a day, five days a week for four weeks (N=7).Bars, SE. FIG. 11D, Nude mice bearing PC-3/TxR tumors were treated withcompound 17ya (PO, 10 mg/kg) three times a week for four weeks (N=5).Bars, SE.

FIG. 12A and FIG. 12B depicts the potent endothelial cell growthinhibition of compound 17ya. Cell growth inhibition of doxorubicin (FIG.12A) and compound 17ya (FIG. 12B) was investigated in several cell linesby SRB study. HUVEC-active and HUVEC-inactive treatments representgrowth factor-supplemented and growth factor-deprived endothelial cellcultures, respectively.

FIGS. 13-13F depicts the disruption of preformed capillary by 17ya.HUVEC cells loaded on Matrigel were allowed to make tube for 16 h andthe test compound was treated to the preformed tubes. The number oftubes (figure A, figure B, and figure C) and nodes (figure D, figure E,and figure F) were counted up to 25 h after drug treatment. Panels A andD are conditions in the presence of CA4, panels B and E are conditionsin the presence of doxorubicin and panels C and F are conditions in thepresence of 17ya.

FIGS. 14A-F depicts the inhibition of the endothelial capillaryformation and disruption of preformed capillaries. Inhibition ofcapillary formation (●) and disruption of preformed capillary (◯) werecompared in an in vitro study using HUVEC cells after 15 h CA4 (figure Aand figure D), DOX (figure B and figure E), and 17ya (figure C andfigure F) treatment. Arrow shows the IC₅₀ value of each compound inHUVEC cell growth inhibition.

FIG. 15 depicts the increased permeability of endothelial cellmonolayers by 17ya and 55. Confluent HUVEC monolayers were exposed totest compound. The leakage of FITC-conjugated dextran through themonolayer was assessed by relative fluorescence measurements at λ=485 nmexcitation and λ=530 nm emission in a receiver to determine changes inmonolayer permeability following exposure.

FIG. 16 depicts in vivo anti-cancer efficacy of 17ya in HL60 leukemiacell xenografts.

FIGS. 17A to 17D provides spectroscopic characteristic of compound 31a.FIG. 17A provides mass spectra. FIGS. 17B to 17D provides the proton NMRspectrum of compound 31a, with the chemical shift axis (x-axis) expandedin FIGS. 17C and 17D.

FIG. 18 depicts metabolic stability in human liver microsomes (HLM),Phase I conditions, of compounds 17ya (▴), 31 (●) and 31a (∘).

FIGS. 19A to 19C depicts pharmacokinetics for 17ya (●) and 31 (●-coloredand ▾) at 5 mg/kg dosages. FIGS. 19A and 19B—rats were administered theindicated doses by injection and the concentration of 17ya and 31 in theblood was determined over time. The upper trace of (●) symbols in FIG.19B correlate with 17ya blood levels when dosed intravenously,indicative of increased in vivo stability for the imidazole. FIG.19C—rats were orally administered 5 mg/kg and the concentration of 17yaand 31 in the blood was determined over time.

FIGS. 20A to 20D depicts in vivo anti-cancer efficacy of compound 17yain PC3 and PC3/TXR (prostate cancer and multidrug-resistant prostatecancer) xenograft studies. FIGS. 20A and 20B: Nude mice bearing PC3(prostate) tumors were orally administered 15 mg/kg 17ya (∘) three timesper week, intravenously administered 7 mg/kg 17ya (Δ) one time per week,or orally administered vehicle alone (●) three times per week, and theeffect on tumor size (FIG. 20A) and body weight (FIG. 20B) was measuredover time. Nude mice bearing PC3/TXR (prostate-paclitaxel-(multidrug)resistant) tumors were orally administered 15 mg/kg 17ya (∘) three timesper week, orally administered vehicle alone (Δ) three times per week, ororally administered vehicle alone (●) one time per week, and the effecton tumor size (FIG. 20C) and body weight (FIG. 20D) was measured overtime.

FIG. 21A and FIG. 21B depicts in vivo anti-cancer efficacy of compound17ya in NCI/ADR-RES (multidrug-resistant ovarian cancer) xenograftstudies. Nude mice bearing NCI/ADR-RES (ovarian adriamycin-(multidrug)resistant) tumors were orally administered 15 mg/kg 17ya (∘) one timeper week, orally administered 15 mg/kg 17ya (Δ) three times per week, ororally administered vehicle alone (●) one time per week, and the effecton tumor size (FIG. 21A) and body weight (FIG. 21B) was measured overtime.

FIG. 22A and FIG. 22B depicts in vivo anti-cancer efficacy of compound17ya in MES-SA/DX5 (multidrug-resistant uterine cancer) xenograftstudies. Nude mice bearing MES-SA/DX5 (uterine doxorubicin-(multidrug)resistant) tumors were orally administered 15 mg/kg 17ya (●) two timesper week, orally administered 20 mg/kg 17ya (●-blue) one time per week,intravenously administered 10 mg/kg DTX (▴-orange) one time per week,orally administered vehicle alone (□) two times per week, or orallyadministered vehicle alone (▪) one time per week, and the effect ontumor size (FIG. 22B) and body weight (FIG. 22A) was measured over time.

FIGS. 23A-22C depicts in vivo anti-cancer efficacy of compound 17ya atdifferent dosages in OVCAR8 (ovarian cancer) xenograft studies. Nudemice bearing OVCAR8 (ovarian) tumors orally administered 20 mg/kg 17ya(●-red) one time per week, intravenously administered 10 mg/kg DTX (∘)one time per week or orally administered vehicle alone (●-black) onetime per week (FIG. 23A), showed minimal reduction of tumor size at the20 mg/kg 17ya dose administered. In contrast, nude mice bearing OVCAR8(ovarian) tumors orally administered 15 mg/kg 17ya (●-red) two times perweek or orally administered vehicle alone (●-black) two times per week(FIG. 23B), showed significant reduction of tumor size using the 15mg/kg 17ya dosage regime. Comparison of body weight over time showed aminimal increase in body weight over the same time period. (FIG. 23C,oral administration of 15 mg/kg 17ya (●-red) two times per week; oraladministrations of vehicle alone (●-black) two times per week)

DETAILED DESCRIPTION OF THE INVENTION

One aspect of the present invention relates to compounds according toformula (I)

wherein

-   -   Q is S, N, or O;    -   X is optional, and can be S═, O═, ═N—NH₂, ═N—OH, or —OH;    -   Y is optional and can be —N(H)—, O, or C₁ to C₂₀ hydrocarbon;        and    -   R₁ and R₂ are each independently substituted or unsubstituted        single-, fused- or multiple-ring aryl or (hetero)cyclic ring        systems, including saturated and unsaturated N-heterocycles,        saturated and unsaturated S-heterocycles, and saturated and        unsaturated O-heterocycles, saturated or unsaturated cyclic        hydrocarbons, saturated or unsaturated mixed heterocycles,        aliphatic straight- or branched-chain C₁ to C₃₀ hydrocarbons.

As used herein, “saturated or unsaturated cyclic hydrocarbons” can beany such cyclic hydrocarbon, including but not limited to phenyl,biphenyl, triphenyl, naphthyl, cycloalkyl, cycloalkenyl, cyclodienyl,fluorene, adamantane, etc.; “saturated or unsaturated N-heterocycles”can be any such N-containing heterocycle, including but not limited toaza- and diaza-cycloalkyls such as aziridinyl, azetidinyl, diazatidinyl,pyrrolidinyl, piperidinyl, piperazinyl, and azocanyl, pyrrolyl,pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl,triazinyl, tetrazinyl, pyrrolizinyl, indolyl, quinolinyl, isoquinolinyl,benzimidazolyl, indazolyl, quinolizinyl, cinnolinyl, quinalolinyl,phthalazinyl, naphthyridinyl, quinoxalinyl, etc.; “saturated orunsaturated O-heterocycles” can be any such O-containing heterocycleincluding but not limited to oxiranyl, oxetanyl, tetrahydrofuranyl,tetrahydropyranyl, dioxanyl, furanyl, pyrylium, benzofuranyl,benzodioxolyl, etc.; “saturated or unsaturated S-heterocycles” can beany such S-containing heterocycle, including but not limited tothiranyl, thietanyl, tetrahydrothiophene-yl, dithiolanyl,tetrahydrothiopyranyl, thiophene-yl, thiepinyl, thianaphthenyl, etc.;“saturated or unsaturated mixed heterocycles” can be any heterocyclecontaining two or more S-, N-, or O-heteroatoms, including but notlimited to oxathiolanyl, morpholinyl, thioxanyl, thiazolyl,isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiaziolyl, etc.

As noted above, the R¹ and R² groups can be substituted orunsubstituted. Thus, although the exemplary groups recited in thepreceding paragraph are unsubstituted, it should be appreciated by thoseof skill in the art that these groups can be substituted by one or more,two or more, three or more, and even up to five substituents (other thanhydrogen). Preferred R¹ and R² groups can be generically represented bythe following structures:

where Z¹ and Z² represent the one or more S-, N-, or O-heteroatomspresent in the cyclic structure, and the rings are five- or six-memberrings. In one embodiment, the R¹ and R² groups can have the structure:

The substituents of these cyclic members (e.g., R³, R⁴, R⁵, R⁶, R⁷) areindependently selected from the group of hydrogen (e.g., no substitutionat a particular position), hydroxyl, an aliphatic straight- orbranched-chain C₁ to C₁₀ hydrocarbon, alkoxy, aryloxy, nitro, cyano,halo (e.g., chloro, fluoro, bromo, or iodo), haloalkyl, dihaloalkyl,trihaloalkyl, amino, alkylamino, mesylamino, dialkylamino, arylamino,amido, urea, alkyl-urea, alkylamido (e.g., acetamide), haloalkylamido,arylamido, aryl, and C₅ to C₇ cycloalkyl, arylalkyl, and combinationsthereof. Single substituents can be present at the ortho, meta, or parapositions. When two or more substituents are present, one of them ispreferably, though not necessarily, at the para position.

As used herein, “aliphatic straight- or branched-chain hydrocarbon”refers to both alkylene groups that contain a single carbon and up to adefined upper limit, as well as alkenyl groups and alkynyl groups thatcontain two carbons up to the upper limit, whether the carbons arepresent in a single chain or a branched chain. Unless specificallyidentified, a hydrocarbon can include up to about 30 carbons, or up toabout 20 hydrocarbons, or up to about 10 hydrocarbons. Alkenyl andalkynyl groups can be mono-unsaturated or polyunsaturated.

As used herein, the term “alkyl” can be any straight- or branched-chainalkyl group containing up to about 30 carbons unless otherwisespecified. The alkyl group can be a sole substituent or it can be acomponent of a larger substituent, such as in an alkoxy, haloalkyl,arylalkyl, alkylamino, dialkylamino, alkylamido, alkylurea, etc.Preferred alkyl groups are methyl, ethyl, and propyl, and thushalomethyl, dihalomethyl, trihalomethyl, haloethyl, dihaloethyl,trihaloethyl, halopropyl, dihalopropyl, trihalopropyl, methoxy, ethoxy,propoxy, arylmethyl, arylethyl, arylpropyl, methylamino, ethylamino,propylamino, dimethylamino, diethylamino, methylamido, acetamido,propylamido, halomethylamido, haloethylamido, halopropylamido,methyl-urea, ethyl-urea, propyl-urea, etc.

As used herein, the term “aryl” refers to any aromatic ring substituentthat is directly bonded to the R¹ or R² ring member(s). The aryl groupcan be a sole substituent, or the aryl group can be a component of alarger substituent, such as in an arylalkyl, arylamino, arylamido, etc.Exemplary aryl groups include, without limitation, phenyl, tolyl, xylyl,furanyl, naphthyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl,triazinyl, thiazolyl, oxazolyl, isooxazolyl, pyrazolyl, imidazolyl,thiophene-yl, pyrrolyl, phenylmethyl, phenylethyl, phenylamino,phenylamido, etc.

As used herein, the term “aminoalkyl” refers to an amine groupsubstituted by an alkyl group as defined above. Aminoalkyl refers tomonoalkylamine, dialkylamine or trialkylamine. Nonlimiting examples ofaminoalkyl groups are —N(Me)₂, —NHMe, —NH₃.

A “haloalkyl” group refers, in another embodiment, to an alkyl group asdefined above, which is substituted by one or more halogen atoms, e.g.by F, Cl, Br or I. Nonlimiting examples of haloalkyl groups are CF₃,CF₂CF₃, CH₂CF₃.

Preferred R¹ and R² groups include substituted (with R³-R⁷ as definedabove) and unsubstituted furanyl, indolyl, pyridinyl, phenyl, biphenyl,triphenyl, diphenylmethane, adamantane-yl, fluorene-yl, and otherheterocyclic analogs such as those identified above (e.g., pyrrolyl,pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl,triazinyl, tetrazinyl, pyrrolizinyl, indolyl, quinolinyl, isoquinolinyl,benzimidazolyl, indazolyl, quinolizinyl, cinnolinyl, quinalolinyl,phthalazinyl, naphthyridinyl, quinoxalinyl, oxiranyl, oxetanyl,tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, furanyl, pyrylium,benzofuranyl, benzodioxolyl, thiranyl, thietanyl,tetrahydrothiophene-yl, dithiolanyl, tetrahydrothiopyranyl,thiophene-yl, thiepinyl, thianaphthenyl, oxathiolanyl, morpholinyl,thioxanyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl,oxadiaziolyl).

The most preferred R² group is 3,4,5-trimethoxyphenyl, and the mostpreferred R¹ groups include substituted and unsubstituted phenyl,substituted and unsubstituted thiophene-yl, and substituted andunsubstituted indolyl groups. The preferred substituents of thesepreferred R¹ groups are methyl, ethyl, fluoro, bromo, cyano, nitro,trifluoromethyl, and amino.

In certain embodiments, the compound of formula (I) is

Depending on the definition of Q, therefore, the compounds of thepresent invention include thiazoles, dihydro-thiazoles, thiazolidines,oxazoles, dihydro-oxazoles, oxazolidines, imidazoles,dihydro-imidazoles, and imidazolidines.

According to a preferred embodiment, the class of compounds has astructure according to formula (II):

where Q and R¹-R⁵ are defined as above for formula (I).

Exemplary compounds of formula (II) include, without limitation:

-   phenyl(2-phenylthiazol-4-yl)methanone (compound 8a);-   phenyl(2-phenylthiazolidin-4-yl)methanone;-   phenyl(2-phenyloxazolidin-4-yl)methanone;-   (4,5-dihydro-2-phenyloxazol-4-yl)(phenyl)methanone;-   phenyl(2-phenyloxazol-4-yl)methanone;-   (4-methoxyphenyl)(2-phenylthiazol-4-yl)methanone (compound 8b);-   (4-methoxyphenyl)(2-phenylthiazolidin-4-yl)methanone;-   (4,5-dihydro-2-phenylthiazol-4-yl)(4-methoxyphenyl)methanone;-   (4-methoxyphenyl)(2-phenyloxazol-4-yl)methanone;-   (4-methoxyphenyl)(2-phenyloxazolidin-4-yl)methanone;-   (4,5-dihydro-2-phenyloxazol-4-yl)(4-methoxyphenyl)methanone;-   (4-methoxyphenyl)(2-phenyl-1H-imidazol-4-yl)methanone;-   (4-methoxyphenyl)(2-phenylimidazolidin-4-yl)methanone;-   (4,5-dihydro-2-phenyl-1H-imidazol-4-yl)(4-methoxyphenyl)methanone;-   (3-methoxyphenyl)(2-phenylthiazol-4-yl)methanone (compound 8c);-   (3-methoxyphenyl)(2-phenylthiazolidin-4-yl)methanone;-   (4,5-dihydro-2-phenylthiazol-4-yl)(3-methoxyphenyl)methanone;-   (3-methoxyphenyl)(2-phenyloxazol-4-yl)methanone;-   (3-methoxyphenyl)(2-phenyloxazolidin-4-yl)methanone;-   (4,5-dihydro-2-phenyloxazol-4-yl)(3-methoxyphenyl)methanone;-   (3-methoxyphenyl)(2-phenyl-1H-imidazol-4-yl)methanone;-   (3-methoxyphenyl)(2-phenylimidazolidin-4-yl)methanone;-   (4,5-dihydro-2-phenyl-1H-imidazol-4-yl)(3-methoxyphenyl)methanone;-   (2-methoxyphenyl)(2-phenylthiazol-4-yl)methanone (compound 8d);-   (2-methoxyphenyl)(2-phenylthiazolidin-4-yl)methanone;-   (4,5-dihydro-2-phenylthiazol-4-yl)(2-methoxyphenyl)methanone;-   (2-methoxyphenyl)(2-phenyloxazol-4-yl)methanone;-   (2-methoxyphenyl)(2-phenyloxazolidin-4-yl)methanone;-   (4,5-dihydro-2-phenyloxazol-4-yl)(2-methoxyphenyl)methanone;-   (2-methoxyphenyl)(2-phenyl-1H-imidazol-4-yl)methanone;-   (2-methoxyphenyl)(2-phenylimidazolidin-4-yl)methanone;-   (4,5-dihydro-2-phenyl-1H-imidazol-4-yl)(2-methoxyphenyl)methanone;-   (3,4-dimethoxyphenyl)(2-phenylthiazol-4-yl)methanone (compound 8e);-   (3,4-dimethoxyphenyl)(2-phenylthiazolidin-4-yl)methanone;-   (4,5-dihydro-2-phenylthiazol-4-yl)(3,4-dimethoxyphenyl)methanone;-   (3,4-dimethoxyphenyl)(2-phenyloxazol-4-yl)methanone;-   (3,4-dimethoxyphenyl)(2-phenyloxazolidin-4-yl)methanone;-   (4,5-dihydro-2-phenyloxazol-4-yl)(3,4-dimethoxyphenyl)methanone;-   (3,4-dimethoxyphenyl)(2-phenyl-1H-imidazol-4-yl)methanone;-   (3,4-dimethoxyphenyl)(2-phenylimidazolidin-4-yl)methanone;-   (4,5-dihydro-2-phenyl-1H-imidazol-4-yl)(3,4-dimethoxyphenyl)methanone;-   (3,4,5-trimethoxyphenyl)(2-phenylthiazol-4-yl)methanone (compound    8f);-   (3,4,5-trimethoxyphenyl)(2-phenylthiazolidin-4-yl)methanone;-   (4,5-dihydro-2-phenylthiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone,    which readily converts to compound 8f;-   (3,4,5-trimethoxyphenyl)(2-phenyloxazolidin-4-yl)methanone;-   (4,5-dihydro-2-phenyloxazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (3,4,5-trimethoxyphenyl)(2-phenyloxazol-4-yl)methanone;-   (4,5-dihydro-2-phenyl-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (3,4,5-trimethoxyphenyl)(2-phenyl-1H-imidazol-4-yl)methanone;-   (3,4,5-trimethoxyphenyl)(2-phenylimidazolidin-4-yl)methanone;-   (3,5-dimethoxyphenyl)(2-phenylthiazol-4-yl)methanone (compound 8g);-   (3,5-dimethoxyphenyl)(2-phenylthiazolidin-4-yl)methanone;-   (4,5-dihydro-2-phenylthiazol-4-yl)(3,5-dimethoxyphenyl)methanone;-   (3,5-dimethoxyphenyl)(2-phenyloxazol-4-yl)methanone;-   (3,5-dimethoxyphenyl)(2-phenyloxazolidin-4-yl)methanone;-   (4,5-dihydro-2-phenyloxazol-4-yl)(3,5-dimethoxyphenyl)methanone;-   (3,5-dimethoxyphenyl)(2-phenyl-1H-imidazol-4-yl)methanone;-   (3,5-dimethoxyphenyl)(2-phenylimidazolidin-4-yl)methanone;-   (4,5-dihydro-2-phenyl-1H-imidazol-4-yl)(3,5-dimethoxyphenyl)methanone;-   (2-fluorophenyl)(2-phenylthiazol-4-yl)methanone (compound 8h);-   (2-fluorophenyl)(2-phenylthiazolidin-4-yl)methanone;-   (4,5-dihydro-2-phenylthiazol-4-yl)(2-fluorophenyl)methanone;-   (2-fluorophenyl)(2-phenyloxazol-4-yl)methanone;-   (2-fluorophenyl)(2-phenyloxazolidin-4-yl)methanone;-   (4,5-dihydro-2-phenyloxazol-4-yl)(2-fluorophenyl)methanone;-   (2-fluorophenyl)(2-phenyl-1H-imidazol-4-yl)methanone;-   (2-fluorophenyl)(2-phenylimidazolidin-4-yl)methanone;-   (4,5-dihydro-2-phenyl-1H-imidazol-4-yl)(2-fluorophenyl)methanone;-   (2-phenylthiazol-4-yl)(pyridin-2-yl)methanone (compound 8i);-   (4,5-dihydro-2-phenylthiazol-4-yl)(pyridin-2-yl)methanone;-   (2-phenylthiazolidin-4-yl)(pyridin-2-yl)methanone;-   (2-phenyloxazol-4-yl)(pyridin-2-yl)methanone;-   (4,5-dihydro-2-phenyloxazol-4-yl)(pyridin-2-yl)methanone;-   (2-phenyloxazolidin-4-yl)(pyridin-2-yl)methanone;-   (2-phenyl-1H-imidazol-4-yl)(pyridin-2-yl)methanone;-   (4,5-dihydro-2-phenyl-1H-imidazol-4-yl)(pyridin-2-yl)methanone;-   (2-phenylimidazolidin-4-yl)(pyridin-2-yl)methanone;-   (2-p-tolylthiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (compound    8k);-   (4,5-dihydro-2-p-tolylthiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (3,4,5-trimethoxyphenyl)(2-p-tolylthiazolidin-4-yl)methanone;-   (2-p-tolyloxazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (4,5-dihydro-2-p-tolyloxazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (3,4,5-trimethoxyphenyl)(2-p-tolyloxazolidin-4-yl)methanone;-   (2-p-tolyl-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (4,5-dihydro-2-p-tolyl-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (3,4,5-trimethoxyphenyl)(2-p-tolylimidazolidin-4-yl)methanone;-   (2-(2-fluorophenyl)-thiazol-4-yl)-(3,4,5-trimethoxyphenyl)methanone    (compound 8l);-   (4,5-dihydro-2-(2-fluorophenyl)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (3,4,5-trimethoxyphenyl)(2-(2-fluorophenyl)thiazolidin-4-yl)methanone;-   (2-(2-fluorophenyl)oxazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (4,5-dihydro-2-(2-fluorophenyl)oxazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (3,4,5-trimethoxyphenyl)(2-(2-fluorophenyl)oxazolidin-4-yl)methanone;-   (2-(2-fluorophenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (4,5-dihydro-2-(2-fluorophenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (3,4,5-trimethoxyphenyl)(2-(2-fluorophenyl)imidazolidin-4-yl)methanone;-   (2-(3-fluorophenyl)-thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone    (compound 8m);-   (4,5-dihydro-2-(3-fluorophenyl)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (3,4,5-trimethoxyphenyl)(2-(3-fluorophenyl)thiazolidin-4-yl)methanone;-   (2-(3-fluorophenyl)oxazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (4,5-dihydro-2-(3-fluorophenyl)oxazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (3,4,5-trimethoxyphenyl)(2-(3-fluorophenyl)oxazolidin-4-yl)methanone;-   (2-(3-fluorophenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (4,5-dihydro-2-(3-fluorophenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (3,4,5-trimethoxyphenyl)(2-(3-fluorophenyl)imidazolidin-4-yl)methanone;-   (2-(4-fluorophenyl)-thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone    (compound 8n);-   (4,5-dihydro-2-(4-fluorophenyl)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (3,4,5-trimethoxyphenyl)(2-(4-fluorophenyl)thiazolidin-4-yl)methanone;-   (2-(4-fluorophenyl)oxazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (4,5-dihydro-2-(4-fluorophenyl)oxazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (3,4,5-trimethoxyphenyl)(2-(4-fluorophenyl)oxazolidin-4-yl)methanone;-   (2-(4-fluorophenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (4,5-dihydro-2-(4-fluorophenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (3,4,5-trimethoxyphenyl)(2-(4-fluorophenyl)imidazolidin-4-yl)methanone;-   (2-(3,4-dimethoxyphenyl)-thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone    (compound 8o);-   (4,5-dihydro-2-(3,4-dimethoxyphenyl)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (3,4,5-trimethoxyphenyl)(2-(3,4-dimethoxyphenyl)thiazolidin-4-yl)methanone;-   (2-(3,4-dimethoxyphenyl)oxazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (4,5-dihydro-2-(3,4-dimethoxyphenyl)oxazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (3,4,5-trimethoxyphenyl)(2-(3,4-dimethoxyphenyl)oxazolidin-4-yl)methanone;-   (2-(3,4-dimethoxyphenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (4,5-dihydro-2-(3,4-dimethoxyphenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (3,4,5-trimethoxyphenyl)(2-(3,4-dimethoxyphenyl)imidazolidin-4-yl)methanone;-   (2-(4-nitrophenyl)-thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone    (compound 8p);-   (4,5-dihydro-2-(4-nitrophenyl)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (3,4,5-trimethoxyphenyl)(2-(4-nitrophenyl)thiazolidin-4-yl)methanone;-   (2-(4-nitrophenyl)oxazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (4,5-dihydro-2-(4-nitrophenyl)oxazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (3,4,5-trimethoxyphenyl)(2-(4-nitrophenyl)oxazolidin-4-yl)methanone;-   (2-(4-nitrophenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (4,5-dihydro-2-(4-nitrophenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (3,4,5-trimethoxyphenyl)(2-(4-nitrophenyl)imidazolidin-4-yl)methanone;-   (2-(4-cyanophenyl)-thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone    (compound 8q);-   (4,5-dihydro-2-(4-cyanophenyl)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (3,4,5-trimethoxyphenyl)(2-(4-cyanophenyl)thiazolidin-4-yl)methanone;-   (2-(4-cyanophenyl)oxazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (4,5-dihydro-2-(4-cyanophenyl)oxazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (3,4,5-trimethoxyphenyl)(2-(4-cyanophenyl)oxazolidin-4-yl)methanone;-   (2-(4-cyanophenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (4,5-dihydro-2-(4-cyanophenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (3,4,5-trimethoxyphenyl)(2-(4-cyanophenyl)imidazolidin-4-yl)methanone;-   4-(4-(3,4,5-trimethoxybenzoyl)-thiazol-2-yl)-benzoic acid (compound    8r);-   4-(4-(3,4,5-trimethoxybenzoyl)-(1,3-dihydro)thiazol-2-yl)-benzoic    acid;-   4-(4-(3,4,5-trimethoxybenzoyl)-4,5-dihydrothiazol-2-yl)benzoic acid;-   4-(4-(3,4,5-trimethoxybenzoyl)-thiazolidin-2-yl)-benzoic acid;-   4-(4-(3,4,5-trimethoxybenzoyl)-oxazol-2-yl)-benzoic acid;-   4-(4-(3,4,5-trimethoxybenzoyl)-(1,3-dihydro)oxazol-2-yl)-benzoic    acid;-   4-(4-(3,4,5-trimethoxybenzoyl)-4,5-dihydrooxazol-2-yl)benzoic acid;-   4-(4-(3,4,5-trimethoxybenzoyl)-oxazolidin-2-yl)-benzoic acid;-   4-(4-(3,4,5-trimethoxybenzoyl)-1H-imidazol-2-yl)-benzoic acid;-   4-(4-(3,4,5-trimethoxybenzoyl)-(1,3-dihydro)-1H-imidazol-2-yl)-benzoic    acid;-   4-(4-(3,4,5-trimethoxybenzoyl)-4,5-dihydrothiazol-2-yl)benzoic acid;-   4-(4-(3,4,5-trimethoxybenzoyl)-imidazolidin-2-yl)-benzoic acid;-   methyl-4-(4-(3,4,5-trimethoxybenzoyl)-thiazol-2-yl)-benzoate    (compound 8s);-   methyl-4-(4-(3,4,5-trimethoxybenzoyl)-(1,3-dihydro)thiazol-2-yl)-benzoate;-   methyl    4-(4-(3,4,5-trimethoxybenzoyl)-4,5-dihydrothiazol-2-yl)benzoate;-   methyl-4-(4-(3,4,5-trimethoxybenzoyl)-thiazolidin-2-yl)-benzoate;-   methyl-4-(4-(3,4,5-trimethoxybenzoyl)-oxazol-2-yl)-benzoate;-   methyl-4-(4-(3,4,5-trimethoxybenzoyl)-(1,3-dihydro)oxazol-2-yl)-benzoate;-   methyl    4-(4-(3,4,5-trimethoxybenzoyl)-4,5-dihydrooxazol-2-yl)benzoate;-   methyl-4-(4-(3,4,5-trimethoxybenzoyl)-oxazolidin-2-yl)-benzoate;-   methyl-4-(4-(3,4,5-trimethoxybenzoyl)-1H-imidazol-2-yl)-benzoate;-   methyl-4-(4-(3,4,5-trimethoxybenzoyl)-(1,3-dihydro)-1H-imidazol-2-yl)-benzoate;-   methyl    4-(4-(3,4,5-trimethoxybenzoyl)-4,5-dihydro-1H-imidazol-2-yl)benzoate;-   methyl-4-(4-(3,4,5-trimethoxybenzoyl)-imidazolidin-2-yl)-benzoate;-   (2-(4-(trifluoromethyl)-phenyl)-thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone    (compound 8t);-   (4,5-dihydro-2-(4-(trifluoromethyl)-phenyl)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (3,4,5-trimethoxyphenyl)(2-(4-cyanophenyl)thiazolidin-4-yl)methanone;-   (2-(4-(trifluoromethyl)-phenyl)oxazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (4,5-dihydro-2-(4-(trifluoromethyl)-phenyl)oxazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (3,4,5-trimethoxyphenyl)(2-(4-(trifluoromethyl)-phenyl)oxazolidin-4-yl)methanone;-   (2-(4-(trifluoromethyl)-phenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (4,5-dihydro-2-(4-(trifluoromethyl)-phenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (3,4,5-trimethoxyphenyl)(2-(4-(trifluoromethyl)-phenyl)imidazolidin-4-yl)methanone;-   (2-(4-bromophenyl)-thiazol-4-yl)-(3,4,5-trimethoxyphenyl)methanone    (compound 8u);-   (4,5-dihydro-2-(4-bromophenyl)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (3,4,5-trimethoxyphenyl)(2-(4-bromophenyl)thiazolidin-4-yl)methanone;-   (2-(4-bromophenyl)oxazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (4,5-dihydro-2-(4-bromophenyl)oxazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (3,4,5-trimethoxyphenyl)(2-(4-bromophenyl)oxazolidin-4-yl)methanone;-   (2-(4-bromophenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (4,5-dihydro-2-(4-bromophenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (3,4,5-trimethoxyphenyl)(2-(4-bromophenyl)imidazolidin-4-yl)methanone;-   (2-(4-ethylphenyl)-thiazol-4-yl)-(3,4,5-trimethoxy-phenyl)methanone    (compound 8v);-   (4,5-dihydro-2-(4-ethylphenyl)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (3,4,5-trimethoxyphenyl)(2-(4-ethylphenyl)thiazolidin-4-yl)methanone;-   (2-(4-ethylphenyl)oxazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (4,5-dihydro-2-(4-ethylphenyl)oxazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (3,4,5-trimethoxyphenyl)(2-(4-ethylphenyl)oxazolidin-4-yl)methanone;-   (2-(4-ethylphenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (4,5-dihydro-2-(4-ethylphenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (3,4,5-trimethoxyphenyl)(2-(4-ethylphenyl)imidazolidin-4-yl)methanone;-   (2-(4-aminophenyl)-thiazol-4-yl)-(3,4,5-trimethoxy-phenyl)methanone    (compound 8w);-   (2-(4-aminophenyl)thiazolidin-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (2-(4-aminophenyl)-4,5-dihydrothiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (2-(4-aminophenyl)-oxazol-4-yl)-(3,4,5-trimethoxyphenyl)methanone;-   (2-(4-aminophenyl)oxazolidin-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (2-(4-aminophenyl)-4,5-dihydrooxazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (2-(4-aminophenyl)-1H-imidazol-4-yl)-(3,4,5-trimethoxy-phenyl)methanone;-   (2-(4-aminophenyl)-1H-imidazolidin-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (2-(4-aminophenyl)-4,5-dihydroimidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (2-(4-acetamidophenyl)thiazolidin-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (2-(4-acetamidophenyl)-4,5-dihydrothiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (2-(4-acetamidophenyl)-thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (3,4,5-trimethoxyphenyl)(2-(3,4,5-trimethoxyphenyl)thiazol-4-yl)methanone;-   (4,5-dihydro-2-(3,4,5-trimethoxyphenyl)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (3,4,5-trimethoxyphenyl)(2-(3,4,5-trimethoxyphenyl)thiazolidin-4-yl)methanone;-   (3,4,5-trimethoxyphenyl)(2-(3,4-dimethoxyphenyl)thiazol-4-yl)methanone;-   (4,5-dihydro-2-(3,4-dimethoxyphenyl)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (3,4,5-trimethoxyphenyl)(2-(3,4-dimethoxyphenyl)thiazolidin-4-yl)methanone;-   (2-(4-fluorophenyl)thiazolidin-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (2-(4-fluorophenyl)-4,5-dihydrothiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (2-(4-fluorophenyl)-thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (3,4,5-trimethoxyphenyl)(2-(2-methoxyphenyl)thiazol-4-yl)methanone;-   (4,5-dihydro-2-(2-methoxyphenyl)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (3,4,5-trimethoxyphenyl)(2-(2-methoxyphenyl)thiazolidin-4-yl)methanone;-   (2-(pyridin-4-yl)-thiazol-4-yl)-(3,4,5-trimethoxyphenyl)methanone    (compound 8x);-   (4,5-dihydro-2-(pyridin-4-yl)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (3,4,5-trimethoxyphenyl)(2-(pyridin-4-yl)thiazolidin-4-yl)methanone;-   (2-(pyridin-4-yl)-oxazol-4-yl)-(3,4,5-trimethoxyphenyl)methanone;-   (4,5-dihydro-2-(pyridin-4-yl)oxazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (3,4,5-trimethoxyphenyl)(2-(pyridin-4-yl)oxazolidin-4-yl)methanone;-   (2-(pyridin-4-yl)-1H-imidazol-4-yl)-(3,4,5-trimethoxyphenyl)methanone;-   (4,5-dihydro-2-(pyridin-4-yl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (3,4,5-trimethoxyphenyl)(2-(pyridin-4-yl)imidazolidin-4-yl)methanone;-   (2-(pyrimidin-2-yl)-thiazol-4-yl)-(3,4,5-trimethoxyphenyl)methanone    (compound 8y);-   (4,5-dihydro-2-(pyrimidin-4-yl)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (3,4,5-trimethoxyphenyl)(2-(pyrimidin-4-yl)thiazolidin-4-yl)methanone;-   (2-(pyrimidin-4-yl)-oxazol-4-yl)-(3,4,5-trimethoxyphenyl)methanone;-   (4,5-dihydro-2-(pyrimidin-4-yl)oxazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (3,4,5-trimethoxyphenyl)(2-(pyrimidin-4-yl)oxazolidin-4-yl)methanone;-   (2-(pyrimidin-4-yl)-1H-imidazol-4-yl)-(3,4,5-trimethoxyphenyl)methanone;-   (4,5-dihydro-2-(pyrimidin-4-yl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (3,4,5-trimethoxyphenyl)(2-(pyrimidin-4-yl)imidazolidin-4-yl)methanone;-   (2-(thiophen-2-yl)-thiazol-4-yl)-(3,4,5-trimethoxyphenyl)methanone    (compound 8z);-   (4,5-dihydro-2-(thiophen-2-yl)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (3,4,5-trimethoxyphenyl)(2-(thiophen-2-yl)thiazolidin-4-yl)methanone;-   (2-(thiophen-2-yl)-oxazol-4-yl)-(3,4,5-trimethoxyphenyl)methanone;-   (4,5-dihydro-2-(thiophen-2-yl)oxazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (3,4,5-trimethoxyphenyl)(2-(thiophen-2-yl)oxazolidin-4-yl)methanone;-   (2-(thiophen-2-yl)-1H-imidazol-4-yl)-(3,4,5-trimethoxyphenyl)methanone;-   (4,5-dihydro-2-(thiophen-2-yl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (3,4,5-trimethoxyphenyl)(2-(thiophen-2-yl)imidazolidin-4-yl)methanone;-   (2-(1H-indol-5-yl)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone    (compound 31);-   [(2-(1-methyl-1H-indol-5-yl)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone](compound    31a);-   (2-(1H-indol-5-yl)thiazolidin-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (4,5-dihydro-2-(1H-indol-5-yl)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (2-(1H-indol-5-yl)oxazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (2-(1H-indol-5-yl)oxazolidin-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (4,5-dihydro-2-(1H-indol-5-yl)oxazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (2-(1H-indol-5-yl)imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (2-(1H-indol-5-yl)imidazolidin-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (4,5-dihydro-2-(1H-indol-5-yl)imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (2-(1H-indol-2-yl)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone    (compound 32);-   (4,5-dihydro-2-(1H-indol-2-yl)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (2-(1H-indol-2-yl)thiazolidin-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (2-(1H-indol-2-yl)oxazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (4,5-dihydro-2-(1H-indol-2-yl)oxazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (2-(1H-indol-2-yl)oxazolidin-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (2-(1H-indol-2-yl)imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (4,5-dihydro-2-(1H-indol-2-yl)imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (2-(1H-indol-2-yl)imidazolidin-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (2-(1H-indol-1-yl)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (4,5-dihydro-2-(1H-indol-1-yl)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (2-(1H-indol-1-yl)thiazolidin-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (2-(1H-indol-1-yl)oxazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (4,5-dihydro-2-(1H-indol-1-yl)oxazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (2-(1H-indol-1-yl)oxazolidin-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (2-(1H-indol-1-yl)imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (4,5-dihydro-2-(1H-indol-1-yl)imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (2-(1H-indol-1-yl)imidazolidin-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (2-(1H-indol-3-yl)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (4,5-dihydro-2-(1H-indol-3-yl)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (2-(1H-indol-3-yl)thiazolidin-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (2-(1H-indol-3-yl)oxazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (4,5-dihydro-2-(1H-indol-3-yl)oxazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (2-(1H-indol-3-yl)oxazolidin-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (2-(1H-indol-3-yl)imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone    (Compound 17ya);-   (4,5-dihydro-2-(1H-indol-3-yl)imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (2-(1H-indol-3-yl)imidazolidin-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (2-(1H-indol-4-yl)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (4,5-dihydro-2-(1H-indol-4-yl)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (2-(1H-indol-4-yl)thiazolidin-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (2-(1H-indol-4-yl)oxazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (4,5-dihydro-2-(1H-indol-4-yl)oxazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (2-(1H-indol-4-yl)oxazolidin-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (2-(1H-indol-4-yl)imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (4,5-dihydro-2-(1H-indol-4-yl)imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (2-(1H-indol-4-yl)imidazolidin-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (2-(1H-indol-6-yl)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (4,5-dihydro-2-(1H-indol-6-yl)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (2-(1H-indol-6-yl)thiazolidin-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (2-(1H-indol-6-yl)oxazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (4,5-dihydro-2-(1H-indol-6-yl)oxazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (2-(1H-indol-6-yl)oxazolidin-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (2-(1H-indol-6-yl)imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (4,5-dihydro-2-(1H-indol-6-yl)imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (2-(1H-indol-6-yl)imidazolidin-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (2-(1H-indol-7-yl)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (4,5-dihydro-2-(1H-indol-7-yl)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (2-(1H-indol-7-yl)thiazolidin-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (2-(1H-indol-7-yl)oxazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (4,5-dihydro-2-(1H-indol-7-yl)oxazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (2-(1H-indol-7-yl)oxazolidin-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (2-(1H-indol-7-yl)imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (4,5-dihydro-2-(1H-indol-7-yl)imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;    and-   (2-(1H-indol-7-yl)imidazolidin-4-yl)(3,4,5-trimethoxyphenyl)methanone.

Preferably, the R¹ group is substituted or unsubstituted phenyl,substituted or unsubstituted thiophene-yl, or substituted orunsubstituted indolyl; and the R² group is 3,4,5-trimethoxyphenyl. Thus,of the above-listed compounds,

-   (3,4,5-trimethoxyphenyl)(2-phenylthiazol-4-yl)methanone (compound    8f);-   (2-p-tolylthiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (compound    8k);-   (2-(4-fluorophenyl)-thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone    (compound 8n);-   (2-(4-nitrophenyl)-thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone    (compound 8p);-   (2-(4-cyanophenyl)-thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone    (compound 8q);-   (2-(4-(trifluoromethyl)-phenyl)-thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone    (compound 8t);-   (2-(4-bromophenyl)-thiazol-4-yl)-(3,4,5-trimethoxyphenyl)methanone    (compound 8u);-   (2-(4-ethylphenyl)-thiazol-4-yl)-(3,4,5-trimethoxy-phenyl)methanone    (compound 8v);-   (2-(4-aminophenyl)-thiazol-4-yl)-(3,4,5-trimethoxy-phenyl)methanone    (compound 8w);-   (2-(thiophen-2-yl)-thiazol-4-yl)-(3,4,5-trimethoxyphenyl)methanone    (compound 8z);-   (2-(1H-indol-5-yl)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone    (compound 31);-   (2-(1-methyl-1H-indol-5-yl)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone)    (compound 31a);-   (2-(1H-indol-2-yl)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone    (compound 32);-   (2-(1H-indol-1-yl)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (2-(1H-indol-3-yl)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (2-(1H-indol-4-yl)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;-   (2-(1H-indol-6-yl)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;    and-   (2-(1H-indol-7-yl)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone are    preferred.

According to another embodiment, the class of compounds has a structureaccording to formula (III):

where Q and R¹-R⁵ are defined as above for formula (I).

Exemplary compounds of formula (III) include, without limitation:

-   3,4,5-trimethoxyphenyl 4,5-dihydro-2-phenylthiazole-4-carboxylate;-   3,4,5-trimethoxyphenyl 2-phenylthiazole-4-carboxylate;-   3,4,5-trimethoxyphenyl 2-phenylthiazolidine-4-carboxylate;-   3,4,5-trimethoxyphenyl 2-phenyloxazolidine-4-carboxylate;-   3,4,5-trimethoxyphenyl 4,5-dihydro-2-phenyloxazole-4-carboxylate;-   3,4,5-trimethoxyphenyl 2-phenyloxazole-4-carboxylate;-   3,4,5-trimethoxyphenyl 2-phenylimidazolidine-4-carboxylate;-   3,4,5-trimethoxyphenyl    4,5-dihydro-2-phenyl-1H-imidazole-4-carboxylate; and-   3,4,5-trimethoxyphenyl 2-phenyl-1H-imidazole-4-carboxylate.

According to another embodiment, the class of compounds has a structureaccording to formula (IV):

where Q and R¹-R⁵ are defined as above for formula (I).

Exemplary compounds of formula (IV) include, without limitation:

-   N-(3,4,5-trimethoxyphenyl)-2-phenyloxazolidine-4-carboxamide;-   4,5-dihydro-N-(3,4,5-trimethoxyphenyl)-2-phenyloxazole-4-carboxamide;-   N-(3,4,5-trimethoxyphenyl)-2-phenyloxazole-4-carboxyamide;-   N-(3,4,5-trimethoxyphenyl)-2-phenyl-1H-imidazole-4-carboxamide;-   4,5-dihydro-N-(3,4,5-trimethoxyphenyl)-2-phenyl-1H-imidazole-4-carboxamide;-   N-(3,4,5-trimethoxyphenyl)-2-phenylimidazolidine-4-carboxamide;-   4,5-dihydro-N-(3,4,5-trimethoxyphenyl)-2-phenylthiazole-4-carboxamide;-   N-(3,4,5-trimethoxyphenyl)-2-phenylthiazole-4-carboxamide; and-   N-(3,4,5-trimethoxyphenyl)-2-phenylthiazolidine-4-carboxamide.

According to another embodiment, the class of compounds has a structureaccording to formula (V):

where Q and R¹-R⁵ are defined as above for formula (I).

Exemplary compounds of formula (V) include, without limitation:

-   4-(3,4,5-trimethoxybenzyl)-2-phenylthiazolidine;-   4-(3,4,5-trimethoxybenzyl)-4,5-dihydro-2-phenylthiazole;-   4-(3,4,5-trimethoxybenzyl)-2-phenylthiazole;-   4-(3,4,5-trimethoxybenzyl)-2-phenyloxazole;-   4-(3,4,5-trimethoxybenzyl)-4,5-dihydro-2-phenyloxazole;-   4-(3,4,5-trimethoxybenzyl)-2-phenyloxazolidine;-   4-(3,4,5-trimethoxybenzyl)-2-phenylimidazolidine;-   4-(3,4,5-trimethoxybenzyl)-4,5-dihydro-2-phenyl-1H-imidazole; and-   4-(3,4,5-trimethoxybenzyl)-2-phenyl-1H-imidazole.

According to another embodiment, the class of compounds has a structureaccording to formula (VI):

where Q and R¹-R⁵ are defined as above for formula (I).

Exemplary compounds of formula (VI) include, without limitation:

-   phenyl(2-phenylthiazolidin-4-yl)methanethione;-   phenyl(2-phenyloxazolidin-4-yl)methanethione;-   (4,5-dihydro-2-phenyloxazol-4-yl)(phenyl)methanethione;-   phenyl(2-phenyloxazol-4-yl)methanethione;-   (3,4,5-trimethoxyphenyl)(2-phenylthiazol-4-yl)methanethione;-   (3,4,5-trimethoxyphenyl)(2-phenylthiazolidin-4-yl)methanethione;-   (3,4,5-trimethoxyphenyl)(2-phenyloxazolidin-4-yl)methanethione;-   (4,5-dihydro-2-phenyloxazol-4-yl)(3,4,5-trimethoxyphenyl)methanethione;-   (3,4,5-trimethoxyphenyl)(2-phenyloxazol-4-yl)methanethione;-   (4,5-dihydro-2-phenyl-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanethione;-   (3,4,5-trimethoxyphenyl)(2-phenyl-1H-imidazol-4-yl)methanethione;    and-   (3,4,5-trimethoxyphenyl)(2-phenylimidazolidin-4-yl)methanethione.

According to another preferred embodiment, the class of compounds has astructure according to formula (VII):

where Q and R¹-R⁵ are defined as above for formula (I).

Exemplary compounds according to formula (VII) include, withoutlimitation,

-   (Z)-1-((3,4,5-trimethoxyphenyl)(2-phenylthiazol-4-yl)methylene)hydrazine    (compound 33);-   (E)-1-((3,4,5-trimethoxyphenyl)(2-phenylthiazol-4-yl)methylene)hydrazine    (compound 34);-   (Z)-1-((4,5-dihydro-2-phenylthiazol-4-yl)(3,4,5-trimethoxyphenyl)methylene)hydrazine;-   (E)-1-((4,5-dihydro-2-phenylthiazol-4-yl)(3,4,5-trimethoxyphenyl)methylene)hydrazine;-   (Z)-1-((3,4,5-trimethoxyphenyl)(2-phenylthiazolidin-4-yl)methylene)hydrazine;-   (E)-1-((3,4,5-trimethoxyphenyl)(2-phenylthiazolidin-4-yl)methylene)hydrazine;-   (Z)-1-((3,4,5-trimethoxyphenyl)(2-phenyloxazol-4-yl)methylene)hydrazine;-   (E)-1-((3,4,5-trimethoxyphenyl)(2-phenyloxazol-4-yl)methylene)hydrazine;-   (Z)-1-((4,5-dihydro-2-phenyloxazol-4-yl)(3,4,5-trimethoxyphenyl)methylene)hydrazine;-   (E)-1-((4,5-dihydro-2-phenyloxazol-4-yl)(3,4,5-trimethoxyphenyl)methylene)hydrazine;-   (Z)-1-((3,4,5-trimethoxyphenyl)(2-phenyloxazolidin-4-yl)methylene)hydrazine;-   (E)-1-((3,4,5-trimethoxyphenyl)(2-phenyloxazolidin-4-yl)methylene)hydrazine;-   (Z)-1-((3,4,5-trimethoxyphenyl)(2-phenyl-1H-imidazol-4-yl)methylene)hydrazine;-   (E)-1-((3,4,5-trimethoxyphenyl)(2-phenyl-1H-imidazol-4-yl)methylene)hydrazine;-   (Z)-1-((4,5-dihydro-2-phenyl-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methylene)    hydrazine;-   (E)-1-((4,5-dihydro-2-phenyl-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methylene)hydrazine;-   (Z)-1-((3,4,5-trimethoxyphenyl)(2-phenylimidazolidin-4-yl)methylene)hydrazine;    and-   (E)-1-((3,4,5-trimethoxyphenyl)(2-phenylimidazolidin-4-yl)methylene)hydrazine.

According to another preferred embodiment, the class of compounds has astructure according to formula (VIII):

where Q and R¹-R⁵ are defined as above for formula (I).

Exemplary compounds according to formula (VIII) include, withoutlimitation,

-   (Z)-(2-phenylthiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone oxime    (compound 35);-   (E)-(2-phenylthiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone oxime    (compound 36);-   (Z)-1-(4,5-dihydro-2-phenylthiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone    oxime;-   (E)-1-(4,5-dihydro-2-phenylthiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone    oxime;-   (Z)-1-(3,4,5-trimethoxyphenyl)(2-phenylthiazolidin-4-yl)methanone    oxime;-   (E)-1-(3,4,5-trimethoxyphenyl)(2-phenylthiazolidin-4-yl)methanone    oxime;-   (Z)-1-(3,4,5-trimethoxyphenyl)(2-phenyloxazol-4-yl)methanone oxime;-   (E)-1-(3,4,5-trimethoxyphenyl)(2-phenyloxazol-4-yl)methanone oxime;-   (Z)-1-(4,5-dihydro-2-phenyloxazol-4-yl)(3,4,5-trimethoxyphenyl)methanone    oxime;-   (E)-1-(4,5-dihydro-2-phenyloxazol-4-yl)(3,4,5-trimethoxyphenyl)methanone    oxime;-   (Z)-1-(3,4,5-trimethoxyphenyl)(2-phenyloxazolidin-4-yl)methanone    oxime;-   (E)-1-(3,4,5-trimethoxyphenyl)(2-phenyloxazolidin-4-yl)methanone    oxime;-   (Z)-1-(3,4,5-trimethoxyphenyl)(2-phenyl-1H-imidazol-4-yl)methanone    oxime;-   (E)-1-(3,4,5-trimethoxyphenyl)(2-phenyl-1H-imidazol-4-yl)methanone    oxime;-   (Z)-1-(4,5-dihydro-2-phenyl-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone    oxime;-   (E)-1-(4,5-dihydro-2-phenyl-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone    oxime;-   (Z)-1-(3,4,5-trimethoxyphenyl)(2-phenylimidazolidin-4-yl)methanone    oxime; and-   (E)-1-(3,4,5-trimethoxyphenyl)(2-phenylimidazolidin-4-yl)methanone    oxime.

In one aspect, the present invention provides a compound of formula XI:

wherein

X is a bond, NH or S;

Q is O, NH or S; and

A is substituted or unsubstituted single-, fused- or multiple-ring arylor (hetero)cyclic ring systems; substituted or unsubstituted, saturatedor unsaturated N-heterocycles; substituted or unsubstituted, saturatedor unsaturated S-heterocycles; substituted or unsubstituted, saturatedor unsaturated O-heterocycles; substituted or unsubstituted, saturatedor unsaturated cyclic hydrocarbons; or substituted or unsubstituted,saturated or unsaturated mixed heterocycles; wherein said A ring isoptionally substituted by 1-5 substituents which are independentlyO-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF₃, CN, —CH₂CN, NH₂,hydroxyl, —(CH₂)_(i)NHCH₃, —(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃,C₁-C₅ linear or branched alkyl, haloalkyl, alkylamino, aminoalkyl,—OCH₂Ph, —NHCO-alkyl, COOH, —C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂ orNO₂; and

i is an integer from 0-5;

or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite,tautomer or isomer.

In one embodiment, the present invention provides a compound of formulaXI, or an N-oxide thereof, or a pharmaceutically acceptable saltthereof.

In one embodiment, the A group is substituted or unsubstituted furanyl,benzofuranyl, benzothiophenyl, indolyl, pyridinyl, phenyl, biphenyl,triphenyl, diphenylmethane, adamantane-yl, fluorene-yl, or otherheterocyclic analogs such as, e.g., pyrrolyl, pyrazolyl, imidazolyl,pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, tetrazinyl,pyrrolizinyl, indolyl, isoquinolinyl, quinolinyl, benzimidazolyl,indazolyl, quinolizinyl, cinnolinyl, quinalolinyl, phthalazinyl,naphthyridinyl, quinoxalinyl, oxiranyl, oxetanyl, tetrahydrofuranyl,tetrahydropyranyl, dioxanyl, furanyl, pyrylium, benzodioxolyl, thiranyl,thietanyl, tetrahydrothiophene-yl, dithiolanyl, tetrahydrothiopyranyl,thiophene-yl, thiepinyl, thianaphthenyl, oxathiolanyl, morpholinyl,thioxanyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl,and oxadiaziolyl.

In one embodiment, the A group is substituted or unsubstituted phenyl.In another embodiment, the A group is phenyl substituted by Cl, F ormethyl. In one embodiment, A is substituted or unsubstitutedisoquinolinyl. In one embodiment, the A group includes substituted orunsubstituted indolyl groups, for example, substituted or unsubstituted3-indolyl, 4-indolyl and 5-indolyl. In another embodiment, the A groupis an indolyl substituted with a methyl. In another embodiment, the Agroup is substituted or unsubstituted 3-indolyl. In certain embodiments,the A group is unsubstituted 3-indolyl. In certain embodiments, the Agroup is unsubstituted 5-indolyl. In certain embodiments, the A group issubstituted 5-indolyl.

In one embodiment, the A group can be substituted or unsubstituted.Thus, although the exemplary groups recited in the preceding paragraphare unsubstituted, it should be appreciated by those of skill in the artthat these groups can be substituted by one or more, two or more, threeor more, and even up to five substituents (other than hydrogen).

In one embodiment, the A group is 3,4,5-trimethoxyphenyl. In anotherembodiment the A group is substituted by alkoxy. In another embodimentthe A group is substituted by methoxy. In another embodiment the A groupis substituted by alkyl. In another embodiment the A group issubstituted by methyl. In another embodiment the A group is substitutedby halogen. In another embodiment, the A group is substituted by F. Inanother embodiment, the A group is substituted by Cl. In anotherembodiment, the A group is substituted by Br.

In one embodiment, the substituents of the A groups of formula XI areindependently selected from the group consisting of hydrogen (e.g., nosubstitution at a particular position), hydroxyl, an aliphatic straight-or branched-chain C₁ to C₁₀ hydrocarbon, alkoxy, haloalkoxy, aryloxy,nitro, cyano, alkyl-CN, halo, haloalkyl, dihaloalkyl, trihaloalkyl,COOH, C(O)Ph, C(O)-alkyl, C(O)O-alkyl, C(O)H, C(O)NH₂, —OC(O)CF₃,—OCH₂Ph, amino, aminoalkyl, alkylamino, mesylamino, dialkylamino,arylamino, amido, NHC(O)-alkyl, urea, alkyl-urea, alkylamido (e.g.,acetamide), haloalkylamido, arylamido, aryl, and C₅ to C₇ cycloalkyl,arylalkyl, and combinations thereof. Single substituents can be presentat the ortho, meta, or para positions. In some embodiments, when two ormore substituents are present, one of them is at the para position.

In one embodiment if Q of Formula XI is S, then X is not a bond.

In one embodiment, Q is NH. In another embodiment, Q is O.

In one embodiment, X is a bond. In another embodiment, X is NH. Incertain embodiments, X is S.

In one embodiment, Q is NH and X is a bond.

In another embodiment, Q is NH, X is a bond and A is a substituted orunsubstituted indolyl. In another embodiment, Q is NH, X is a bond and Ais a substituted or unsubstituted 3-indolyl.

In another aspect, this invention provides a compound of formula XI(e):

wherein R₄ and R₅ are independently hydrogen, O-alkyl, O-haloalkyl, F,Cl, Br, I, haloalkyl, CF₃, CN, —CH₂CN, NH₂, hydroxyl, —(CH₂)_(i)NHCH₃,—(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃, C₁-C₅ linear or branchedalkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl, COOH,—C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂ or NO₂;

R₉ and R₁ are independently H, linear or branched, substituted orunsubstituted alkyl, substituted or unsubstituted aryl, —CH₂Ph,substituted benzyl, haloalkyl, aminoalkyl, —OCH₂Ph, substituted orunsubstituted SO₂-aryl, substituted or unsubstituted —(C═O)-aryl or OH;

i is an integer from 0-5; and

n is an integer between 1-3;

or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite,tautomer or isomer.

In one embodiment, the present invention provides a compound of formulaXI(e), or an N-oxide thereof, or a pharmaceutically acceptable saltthereof.

In one embodiment, n is 1. In another embodiment, n is 2.

In one embodiment, R₄ and R₅ are independently H.

In another embodiment, R₄ and R₅ of formula XI(e) are independently H,O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CN, NH₂, or OH. In oneembodiment, R₄ and R₅ are independently H, OCH₃, F, Cl, CF₃, or OH. Incertain embodiments, R₄ and R₅ are independently H or OCH₃. In anotherembodiment, R₄ and R₅ are independently H, F, or Cl. In anotherembodiment, R₄ and R₅ are independently H or CF₃. In another embodiment,R₄ and R₅ are independently H or OH.

In another embodiment, R₁ and R₉ of formula XI(e) are independently areindependently H, linear or branched, substituted or unsubstituted alkyl,substituted or unsubstituted aryl, —CH₂Ph, substituted benzyl,haloalkyl, aminoalkyl, —OCH₂Ph, substituted or unsubstituted SO₂-aryl,substituted or unsubstituted —(C═O)-aryl or OH. In one embodiment, R₁and R₉ are independently hydrogen. In one embodiment, R₁ and R₉ areindependently branched, substituted or unsubstituted alkyl. In oneembodiment, R₁ and R₉ are independently substituted or unsubstitutedaryl. In one embodiment, R₁ and R₉ are independently —CH₂Ph. In oneembodiment, R₁ and R₉ are independently substituted benzyl. In oneembodiment, R₁ and R₉ are independently haloalkyl. In one embodiment, R₁and R₉ are independently aminoalkyl. In one embodiment, R₁ and R₉ areindependently —OCH₂Ph. In one embodiment, R₁ and R₉ are independentlysubstituted or unsubstituted SO₂-aryl. In one embodiment, R₁ and R₉ areindependently hydrogen or substituted or unsubstituted —(C═O)-aryl. Inone embodiment, R₁ and R₉ are independently OH.

In another aspect, the present invention provides a compound of formula(17ya):

In another embodiment, a compound of formula XI(e) is represented by thestructure of compound 17yab:

In another embodiment, a compound of formula XI(e) is represented by thestructure of compound 17yac:

In another aspect, the present invention provides a compound of formulaXXI:

wherein

A is indolyl;

Q is NH, O or S;

R₁ and R₂ are independently H, O-alkyl, I, Br, Cl, F, alkyl, haloalkyl,aminoalkyl, —(CH₂)_(i)NHCH₃, —(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OCH₂Ph,OH, CN, NO₂, —NHCO-alkyl, COOH, C(O)O-alkyl or C(O)H; and

wherein said A is optionally substituted by substituted or unsubstitutedO-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF₃, CN, —CH₂CN, NH₂,hydroxyl, —(CH₂)_(i)NHCH₃, —(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃,substituted or unsubstituted —SO₂-aryl, substituted or unsubstitutedC₁-C₅ linear or branched alkyl, substituted or unsubstituted haloalkyl,substituted or unsubstituted alkylamino, substituted or unsubstitutedaminoalkyl, —OCH₂Ph, substituted or unsubstituted —NHCO-alkyl, COOH,substituted or unsubstituted —C(O)Ph, substituted or unsubstitutedC(O)O-alkyl, C(O)H, —C(O)NH₂, NO₂ or combination thereof;

i is an integer between 0-5; and

m is an integer between 1-4;

or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite,tautomer or isomer.

In one embodiment, the present invention provides a compound of formula(XXI), or an N-oxide thereof, or a pharmaceutically acceptable saltthereof.

In one embodiment, R₁ of compound of formula XXI is OCH₃; m is 3 and R₂is hydrogen. In another embodiment, R₁ is F; m is 1 and R₂ is hydrogen.

In one embodiment, Q of formula XXI is O. In another embodiment Q offormula XXI is NH. In another embodiment, Q of formula XXI is S.

In one embodiment, A ring of compound of formula XXI is substituted5-indolyl. In another embodiment, the substitution is —(C═O)-aryl. Inanother embodiment, the aryl is 3,4,5-(OCH₃)₃-Ph. In another embodiment,the substitution is methyl.

In another embodiment, A ring of compound of formula XXI is 3-indolyl.In another embodiment, A ring of compound of formula XXI is 5-indolyl.In another embodiment, A ring of compound of formula XXI is 2-indolyl.Non limiting examples of compounds of formula XXI are selected from:

-   (5-(4-(3,4,5-trimethoxybenzoyl)-1H-imidazol-2-yl)-1H-indol-2-yl)(3,4,5-trimethoxyphenyl)methanone    (15xaa);-   (1-(phenylsulfonyl)-2-(1-(phenylsulfonyl)-2-(3,4,5-trimethoxybenzoyl)-1H-indol-5-yl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone    (16xaa);-   2-(1H-indol-3-yl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone    (17ya);-   (2-(1H-indol-2-yl)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone    (32);-   (2-(1H-indol-5-yl)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone    (31); and-   (2-(1-methyl-1H-indol-5-yl)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone)]    (31a).

In another aspect, the present invention provides a compound of formulaXXIa:

wherein

W is C═O, C═S, SO₂, S═O;

A is indolyl;

R₁ and R₂ are independently H, O-alkyl, I, Br, Cl, F, alkyl, haloalkyl,aminoalkyl, —(CH₂)_(i)NHCH₃, —(CH₂)_(i)NH₂, —(CH₂)N(CH₃)₂, —OCH₂Ph, OH,CN, NO₂, —NHCO-alkyl, COOH, C(O)O-alkyl or C(O)H;

R₇ and R₈ are independently H, O-alkyl, I, Br, Cl, F, alkyl, haloalkyl,aminoalkyl, —(CH₂)NHCH₃, —(CH₂)NH₂, —(CH₂)N(CH₃)₂, —OCH₂Ph, OH, CN, NO₂,—NHCO-alkyl, COOH, C(O)O-alkyl or C(O)H;

wherein said A is optionally substituted by substituted or unsubstitutedO-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF₃, CN, —CH₂CN, NH₂,hydroxyl, —(CH₂)_(i)NHCH₃, —(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃,substituted or unsubstituted —SO₂-aryl, substituted or unsubstitutedC₁-C₅ linear or branched alkyl, substituted or unsubstituted haloalkyl,substituted or unsubstituted alkylamino, substituted or unsubstitutedaminoalkyl, —OCH₂Ph, substituted or unsubstituted —NHCO-alkyl, COOH,substituted or unsubstituted —C(O)Ph, substituted or unsubstitutedC(O)O-alkyl, C(O)H, —C(O)NH₂, NO₂ or combination thereof;

i is an integer between 0-5; and

m is an integer between 1-3;

q is an integer between 1-3;

or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite,tautomer or isomer.

In one embodiment, the invention provides a compound of formula (XXIa),or an N-oxide thereof, or a pharmaceutically acceptable salt thereof.

In one embodiment, R₁ of compound of formula XXIa is OCH₃; m is 3 and R₂is hydrogen. In another embodiment, R₁ is F; m is 1 and R₂ is hydrogen.

In another embodiment, A ring of compound of formula XXIa is substituted5-indolyl. In another embodiment, A ring of compound of formula XXIa is3-indolyl. Non limiting examples of compounds of formula XXIa areselected from:

-   (1-(phenylsulfonyl)-2-(1-(phenylsulfonyl)-2-(3,4,5-trimethoxybenzoyl)-1H-indol-5-yl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone    (16xaa); and-   (1-(phenylsulfonyl)-2-(1-(phenylsulfonyl)-1H-indol-3-yl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone    (17yaa).

In another aspect, the present invention provides a compound of formulaXXII:

wherein

A is indolyl;

wherein said A is optionally substituted by substituted or unsubstitutedO-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF₃, CN, —CH₂CN, NH₂,hydroxyl, —(CH₂)_(i)NHCH₃, —(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃,substituted or unsubstituted —SO₂-aryl, substituted or unsubstitutedC₁-C₅ linear or branched alkyl, substituted or unsubstituted haloalkyl,substituted or unsubstituted alkylamino, substituted or unsubstitutedaminoalkyl, —OCH₂Ph, substituted or unsubstituted —NHCO-alkyl, COOH,substituted or unsubstituted —C(O)Ph, substituted or unsubstitutedC(O)O-alkyl, C(O)H, —C(O)NH₂, NO₂ or combination thereof;

i is an integer between 0-5;

R₁ is hydrogen, linear or branched, substituted or unsubstituted alkyl,substituted or unsubstituted aryl, —CH₂Ph, substituted benzyl,haloalkyl, aminoalkyl, —OCH₂Ph, substituted or unsubstituted SO₂-aryl,substituted or unsubstituted —(C═O)-aryl or OH;

or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite,tautomer or isomer.

In one embodiment, the invention provides a compound of formula XXII, oran N-oxide thereof, or a pharmaceutically acceptable salt thereof.

In one embodiment, A ring of compound of formula XXII is substituted5-indolyl. In another embodiment the substitution is —(C═O)-aryl. Inanother embodiment, the aryl is 3,4,5-(OCH₃)₃-Ph.

In another embodiment, A ring of compound of formula XXII is substituted3-indolyl. In another embodiment, A ring of compound of formula XXII is3-indolyl. Non limiting examples of compounds of formula XXII areselected from:

-   (5-(4-(3,4,5-trimethoxybenzoyl)-1H-imidazol-2-yl)-1H-indol-2-yl)(3,4,5-trimethoxyphenyl)methanone    (15xaa); and-   (2-(1H-indol-3-yl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone    (17ya).

In another aspect, the present invention provides a compound of formula(17ya):

In one embodiment, this invention provides a compound of this inventionor its isomer, metabolite, pharmaceutically acceptable salt,pharmaceutical product, tautomer, hydrate, N-oxide, polymorph, orcrystal or combinations thereof. In one embodiment, this inventionprovides an isomer of the compound of this invention. In anotherembodiment, this invention provides a metabolite of the compound of thisinvention. In another embodiment, this invention provides apharmaceutically acceptable salt of the compound of this invention. Inanother embodiment, this invention provides a pharmaceutical product ofthe compound of this invention. In another embodiment, this inventionprovides a tautomer of the compound of this invention. In anotherembodiment, this invention provides a hydrate of the compound of thisinvention. In another embodiment, this invention provides an N-oxide ofthe compound of this invention. In another embodiment, this inventionprovides a polymorph of the compound of this invention. In anotherembodiment, this invention provides a crystal of the compound of thisinvention. In another embodiment, this invention provides compositioncomprising a compound of this invention, as described herein, or, inanother embodiment, a combination of an isomer, metabolite,pharmaceutically acceptable salt, pharmaceutical product, tautomer,hydrate, N-oxide, polymorph, or crystal of the compound of thisinvention.

In another embodiment, the invention provides a compound of thisinvention or an N-oxide thereof, or a pharmaceutically acceptable saltthereof.

In one embodiment, this invention provides a compound of formula 17ya orits isomer, metabolite, pharmaceutically acceptable salt, pharmaceuticalproduct, tautomer, hydrate, N-oxide, polymorph, or crystal orcombinations thereof. In one embodiment, this invention provides anisomer of a compound of formula 17ya. In another embodiment, thisinvention provides a metabolite of a compound of formula 17ya. Inanother embodiment, this invention provides a pharmaceuticallyacceptable salt of a compound of formula 17ya. In another embodiment,this invention provides a pharmaceutical product of a compound offormula 17ya. In another embodiment, this invention provides a tautomerof a compound of formula 17ya. In another embodiment, this inventionprovides a hydrate of a compound of formula 17ya. In another embodiment,this invention provides an N-oxide of a compound of formula 17ya. Inanother embodiment, this invention provides a polymorph of a compound offormula 17ya. In another embodiment, this invention provides a crystalof a compound of formula 17ya. In another embodiment, this inventionprovides composition comprising a compound of formula 17ya, as describedherein, or, in another embodiment, a combination of an isomer,metabolite, pharmaceutically acceptable salt, pharmaceutical product,tautomer, hydrate, N-oxide, polymorph, or crystal of a compound offormula 17ya.

In another embodiment, the invention provides a compound of formula 17yaor an N-oxide thereof, or a pharmaceutically acceptable salt thereof.

In one embodiment, the term “isomer” includes, but is not limited to,optical isomers and analogs, structural isomers and analogs,conformational isomers and analogs, and the like.

In one embodiment, the compounds of this invention are the pure(E)-isomers. In another embodiment, the compounds of this invention arethe pure (Z)-isomers. In another embodiment, the compounds of thisinvention are a mixture of the (E) and the (Z) isomers. In oneembodiment, the compounds of this invention are the pure (R)-isomers. Inanother embodiment, the compounds of this invention are the pure(S)-isomers. In another embodiment, the compounds of this invention area mixture of the (R) and the (S) isomers.

The compounds of the present invention can also be present in the formof a racemic mixture, containing substantially equivalent amounts ofstereoisomers. In another embodiment, the compounds of the presentinvention can be prepared or otherwise isolated, using known procedures,to obtain a stereoisomer substantially free of its correspondingstereoisomer (i.e., substantially pure). By substantially pure, it isintended that a stereoisomer is at least about 95% pure, more preferablyat least about 98% pure, most preferably at least about 99% pure.

Compounds of the present invention can also be in the form of a hydrate,which means that the compound further includes a stoichiometric ornon-stoichiometric amount of water bound by non-covalent intermolecularforces.

Compounds of the present invention may exist in the form of one or moreof the possible tautomers and depending on the particular conditions itmay be possible to separate some or all of the tautomers into individualand distinct entities. It is to be understood that all of the possibletautomers, including all additional enol and keto tautomers and/orisomers are hereby covered. For example the following tautomers, but notlimited to these, are included.

The tautomers of this invention are freely interconverting tautomers,not unresolved mixtures. The imidazoles and other ring systems of thisinvention are tautomerizable. All tautomers are considered as part ofthe invention.

The invention includes “pharmaceutically acceptable salts” of thecompounds of this invention, which may be produced, by reaction of acompound of this invention with an acid or base. Certain compounds,particularly those possessing acid or basic groups, can also be in theform of a salt, preferably a pharmaceutically acceptable salt. The term“pharmaceutically acceptable salt” refers to those salts that retain thebiological effectiveness and properties of the free bases or free acids,which are not biologically or otherwise undesirable. The salts areformed with inorganic acids such as hydrochloric acid, hydrobromic acid,sulfuric acid, nitric acid, phosphoric acid and the like, and organicacids such as acetic acid, propionic acid, glycolic acid, pyruvic acid,oxylic acid, maleic acid, malonic acid, succinic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,salicylic acid, N-acetylcysteine and the like. Other salts are known tothose of skill in the art and can readily be adapted for use inaccordance with the present invention.

Suitable pharmaceutically-acceptable salts of amines of the compounds ofthis invention may be prepared from an inorganic acid or from an organicacid. In one embodiment, examples of inorganic salts of amines arebisulfates, borates, bromides, chlorides, hemisulfates, hydrobromates,hydrochlorates, 2-hydroxyethylsulfonates (hydroxyethanesulfonates),iodates, iodides, isothionates, nitrates, persulfates, phosphate,sulfates, sulfamates, sulfanilates, sulfonic acids (alkylsulfonates,arylsulfonates, halogen substituted alkylsulfonates, halogen substitutedarylsulfonates), sulfonates and thiocyanates.

In one embodiment, examples of organic salts of amines may be selectedfrom aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic,carboxylic and sulfonic classes of organic acids, examples of which areacetates, arginines, aspartates, ascorbates, adipates, anthranilates,algenates, alkane carboxylates, substituted alkane carboxylates,alginates, benzenesulfonates, benzoates, bisulfates, butyrates,bicarbonates, bitartrates, citrates, camphorates, camphorsulfonates,cyclohexylsulfamates, cyclopentanepropionates, calcium edetates,camsylates, carbonates, clavulanates, cinnamates, dicarboxylates,digluconates, dodecylsulfonates, dihydrochlorides, decanoates,enanthuates, ethanesulfonates, edetates, edisylates, estolates,esylates, fumarates, formates, fluorides, galacturonates gluconates,glutamates, glycolates, glucorate, glucoheptanoates, glycerophosphates,gluceptates, glycollylarsanilates, glutarates, glutamate, heptanoates,hexanoates, hydroxymaleates, hydroxycarboxlic acids, hexylresorcinates,hydroxybenzoates, hydroxynaphthoates, hydrofluorates, lactates,lactobionates, laurates, malates, maleates,methylenebis(beta-oxynaphthoate), malonates, mandelates, mesylates,methane sulfonates, methylbromides, methylnitrates, methylsulfonates,monopotassium maleates, mucates, monocarboxylates,naphthalenesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates,napsylates, N-methylglucamines, oxalates, octanoates, oleates, pamoates,phenylacetates, picrates, phenylbenzoates, pivalates, propionates,phthalates, phenylacetate, pectinates, phenylpropionates, palmitates,pantothenates, polygalacturates, pyruvates, quinates, salicylates,succinates, stearates, sulfanilate, subacetates, tartrates,theophyllineacetates, p-toluenesulfonates (tosylates),trifluoroacetates, terephthalates, tannates, teoclates, trihaloacetates,triethiodide, tricarboxylates, undecanoates and valerates.

In one embodiment, examples of inorganic salts of carboxylic acids orhydroxyls may be selected from ammonium, alkali metals to includelithium, sodium, potassium, cesium; alkaline earth metals to includecalcium, magnesium, aluminium; zinc, barium, cholines, quaternaryammoniums.

In another embodiment, examples of organic salts of carboxylic acids orhydroxyl may be selected from arginine, organic amines to includealiphatic organic amines, alicyclic organic amines, aromatic organicamines, benzathines, t-butylamines, benethamines(N-benzylphenethylamine), dicyclohexylamines, dimethylamines,diethanolamines, ethanolamines, ethylenediamines, hydrabamines,imidazoles, lysines, methylamines, meglamines, N-methyl-D-glucamines,N,N′-dibenzylethylenediamines, nicotinamides, organic amines,ornithines, pyridines, picolies, piperazines, procain,tris(hydroxymethyl)methylamines, triethylamines, triethanolamines,trimethylamines, tromethamines and ureas.

In one embodiment, the salts may be formed by conventional means, suchas by reacting the free base or free acid form of the product with oneor more equivalents of the appropriate acid or base in a solvent ormedium in which the salt is insoluble or in a solvent such as water,which is removed in vacuo or by freeze drying or by exchanging the ionsof a existing salt for another ion or suitable ion-exchange resin.

The compounds of the present invention may also be administered asprodrugs. Thus, certain derivatives which may have little or nopharmacological activity themselves can, when administered into or ontothe body, be converted into compounds of the present invention havingthe desired activity, for example, by hydrolytic cleavage. Furtherinformation on the use of prodrugs may be found in Pro-drugs as NovelDelivery Systems, Vol. 14, ACS Symposium Series (Higuchi and Stella);and Bioreversible Carriers in Drug Design, Pergamon Press (ed. E BRoche, American Pharmaceutical Association) (1987), each of which ishereby incorporated by reference in its entirety.

Prodrugs can, for example, be produced by replacing appropriatefunctionalities present in the compounds of the present invention withcertain moieties known to those skilled in the art as pro-moieties.Examples of such prodrugs include, without limitation, replacement ofhydrogen in an alcohol functionality (—OH) by a C1 to C6 alkyl to forman ether; and (ii) replacement of hydrogen in a secondary aminofunctionality with a C1 to C10 alkanoyl to form an amide.

A further aspect of the present invention relates to a method of makingthe compounds according to formula (I). Furthermore, the presentinvention discloses synthetic methodologies for the preparation ofamide, alkoxyamides, ketone, hydrazine, and oxime derivatives ofthiazolidines, thiazolines, thiazoles, imidazolines, imidazoles,oxazolidines, oxazolines, and oxazoles.

To synthesize thiazoline and thiazole series compounds, L- or D-cysteinecan be reacted with substituted or unsubstituted benzonitrile inmethanol and pH 6.4 phosphate buffer solution at ambient temperature forseveral days (Bergeron et al., “Evaluation of Desferrithiocin and itsSynthetic Analogs as Orally Effective Iron Chelators,” J. Med Chem.34:2072-8 (1991); Bergeron et al., “DesazadesmethyldesferrithiocinAnalogues as Orally Effective Iron Chelators,” J. Med Chem. 42:95-108(1999); Zamri et al., “An Improved Stereocontrolled Synthesis ofPyochelin, Siderophore of Pseudomonas aeruginosa and Burkholderiacepacia,” Tetrahedron 56:249-256 (2000), each of which is herebyincorporated by reference in its entirety). The resulting carboxylicacid intermediates can be easily converted to corresponding Weinrebamides (Nahm et al., “N-Methoxy-N-methylamides as Effective AcylatingAgents,” Tetrahedron Lett. 22:3815-18 (1981), which is herebyincorporated by reference in its entirety) using EDCI/HOBt as couplingreagents. Thiazole intermediates can be obtained from BrCCl₃/DBUdehydrogenation of the Weinreb amides. The thiazole intermediates can bereacted with appropriate lithium reagents or Grignard reagents (i.e.,bearing the corresponding “C” ring, see Scheme 3 infra) in anhydrous THFto give the final thiazoles (Nahm et al., “N-Methoxy-N-methylamides asEffective Acylating Agents,” Tetrahedron Lett. 22:3815-18 (1981), whichis hereby incorporated by reference in its entirety). Alternatively, thethiazoline Weinreb amides can be reacted directly with appropriatelithium reagents or Grignard reagents, after quenching with saturatedNH₄Cl solution, which affords mixtures of thiazoline compounds and thecorresponding thiazole compounds.

When thiazoline/thiazole mixtures were placed in the solvent and exposedto air under ambient atmosphere for some time (overnight to severaldays), the thiazoline ring spontaneously dehydrogenated to thiazoles. Asan example, in solution with deuterated chloroform, mixtures ofthiazoline/thiazole compounds can be slowly converted to almost purethiazole compounds after roughly 9 days (see, e.g., FIG. 2).

Formation of thiazolidine compounds is described in U.S. Pat. No.7,307,093 to Miller et al. and U.S. Pat. No. 7,662,842 to Miller et al.,each of which is hereby incorporated by reference in its entirety.

Oxazoline derivatives (carboxylic acids, carboxamides, methanones)according to the present invention are prepared via condensation ofimine derivatives (benzonitrile and 1-phenyl-2-methoxy-ethanimine) withenantioneric (L or D) or racemic cysteine or serine ester while usingtriethylamine as a base (Meyer et al., Tetrahedron: Asymmetry14:2229-2238 (2003), which is hereby incorporated by reference in itsentirety).

Imidazoline derivatives are prepared using L-tartaric acid in acondensation reaction with substituted or unsubstituted arylaldehyde toform the imidazoline ring system (Anderson et al., J. Med. Chem. 32(1),119-127 (1989), which is hereby incorporated by reference in itsentirety).

Syntheses of thiazole, oxazole, and imidazole can be carried out bydehydrogenation of corresponding thiazoline, oxazoline, and imidazoline.Dehydrogenation according to the present invention can be achieved byinitial halogenation of these core ring systems (thiazoline,imidazoline, and oxazoline) followed by elimination to yield the desiredthiazole, oxazole, and imidazole derivatives.

Formation of thiocarbonyl linker group (from carbonyl) can be carriedout using Lawesson's reagent (Jesberger et al., Synthesis 1929-1958(2003), which is hereby incorporated by reference in its entirety). Thethioketone structure with conjugated aromatic rings is stable relativeto unhindered thioketones.

The carbonyl linker group can also be reduced to an alcohol usingGrignard reaction of an intermediate aldehyde with according Grignardreagents. Alternatively, the carbonyl group can be completely removedwith Clemmensen reduction to form the corresponding hydrocarbon (e.g.,methylene group). When carbonyl is reduced to an alcohol or methylene,the strong hydrogen acceptor C═O reverses to strong hydrogen donor O—Hor hydrocarbon, which totally loses hydrogen bond effects.

The ester and carboxamide linkages can be prepared from the sameintermediate acids used to form the ketone linkage, except that thereactants (acid and “C” ring precursor) are exposed to suitableconditions for formation of the respective ester (DCC, NMM) or amide(EDCl, HOBt, Et₃N) linkages. Carboxamide linkages are also taught inU.S. Pat. No. 7,307,093 to Miller et al. and U.S. Pat. No. 7,662,842 toMiller et al., each of which is hereby incorporated by reference in itsentirety.

It is also appreciated that the compounds and synthetic intermediates ofthe present invention can be prepared by synthetic processes known tothose skilled in the art. Functional groups of intermediates andcompounds of the present invention may need to be protected by suitableprotecting groups. Such functional groups include hydroxy, amino,mercapto and carboxylic acid. Suitable protecting groups for hydroxyinclude trialkylsilyl or diarylalkylsilyl (e.g., t-butyldimethylsilyl,t-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, andthe like. Suitable protecting groups for amino, amidino and guanidinoinclude t-butoxycarbonyl (t-Boc or Boc), benzyloxycarbonyl,phenylsulfonyl, and the like. Suitable protecting groups for mercaptoinclude —C(O)—R (where R is alkyl, aryl or aralkyl), p-methoxybenzyl,trityl and the like. Suitable protecting groups for carboxylic acidinclude alkyl, aryl or aralkyl esters.

Protecting groups may be added or removed in accordance with standardtechniques, which are well-known to those skilled in the art and asdescribed herein. The use of protecting groups is described in detail inGreen et al., Protective Groups in Organic Synthesis, 2nd Ed.,Wiley-Interscience (1991), which is hereby incorporated by reference inits entirety.

Pharmaceutical Composition

Another aspect of the present invention relates to a pharmaceuticalcomposition including a pharmaceutically acceptable carrier and acompound according to the aspects of the present invention. Thepharmaceutical composition can contain one or more of theabove-identified compounds of the present invention. Typically, thepharmaceutical composition of the present invention will include acompound of the present invention or its pharmaceutically acceptablesalt, as well as a pharmaceutically acceptable carrier. The term“pharmaceutically acceptable carrier” refers to any suitable adjuvants,carriers, excipients, or stabilizers, and can be in solid or liquid formsuch as, tablets, capsules, powders, solutions, suspensions, oremulsions.

Typically, the composition will contain from about 0.01 to 99 percent,preferably from about 20 to 75 percent of active compound(s), togetherwith the adjuvants, carriers and/or excipients. While individual needsmay vary, determination of optimal ranges of effective amounts of eachcomponent is within the skill of the art. Typical dosages comprise about0.01 to about 100 mg/kg body wt. The preferred dosages comprise about0.1 to about 100 mg/kg body wt. The most preferred dosages compriseabout 1 to about 100 mg/kg body wt. Treatment regimen for theadministration of the compounds of the present invention can also bedetermined readily by those with ordinary skill in art. That is, thefrequency of administration and size of the dose can be established byroutine optimization, preferably while minimizing any side effects.

The solid unit dosage forms can be of the conventional type. The solidform can be a capsule and the like, such as an ordinary gelatin typecontaining the compounds of the present invention and a carrier, forexample, lubricants and inert fillers such as, lactose, sucrose, orcornstarch. In another embodiment, these compounds are tabulated withconventional tablet bases such as lactose, sucrose, or cornstarch incombination with binders like acacia, cornstarch, or gelatin,disintegrating agents, such as cornstarch, potato starch, or alginicacid, and a lubricant, like stearic acid or magnesium stearate.

The tablets, capsules, and the like can also contain a binder such asgum tragacanth, acacia, corn starch, or gelatin; excipients such asdicalcium phosphate; a disintegrating agent such as corn starch, potatostarch, alginic acid; a lubricant such as magnesium stearate; and asweetening agent such as sucrose, lactose, or saccharin. When the dosageunit form is a capsule, it can contain, in addition to materials of theabove type, a liquid carrier such as a fatty oil.

Various other materials may be present as coatings or to modify thephysical form of the dosage unit. For instance, tablets can be coatedwith shellac, sugar, or both. A syrup can contain, in addition to activeingredient, sucrose as a sweetening agent, methyl and propylparabens aspreservatives, a dye, and flavoring such as cherry or orange flavor.

For oral therapeutic administration, these active compounds can beincorporated with excipients and used in the form of tablets, capsules,elixirs, suspensions, syrups, and the like. Such compositions andpreparations should contain at least 0.1% of active compound. Thepercentage of the compound in these compositions can, of course, bevaried and can conveniently be between about 2% to about 60% of theweight of the unit. The amount of active compound in suchtherapeutically useful compositions is such that a suitable dosage willbe obtained. Preferred compositions according to the present inventionare prepared so that an oral dosage unit contains between about 1 mg and800 mg of active compound.

The active compounds of the present invention may be orallyadministered, for example, with an inert diluent, or with an assimilableedible carrier, or they can be enclosed in hard or soft shell capsules,or they can be compressed into tablets, or they can be incorporateddirectly with the food of the diet.

The pharmaceutical forms suitable for injectable use include sterileaqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In all cases, the form should be sterile and should befluid to the extent that easy syringability exists. It should be stableunder the conditions of manufacture and storage and should be preservedagainst the contaminating action of microorganisms, such as bacteria andfungi. The carrier can be a solvent or dispersion medium containing, forexample, water, ethanol, polyol (e.g., glycerol, propylene glycol, andliquid polyethylene glycol), suitable mixtures thereof, and vegetableoils.

The compounds or pharmaceutical compositions of the present inventionmay also be administered in injectable dosages by solution or suspensionof these materials in a physiologically acceptable diluent with apharmaceutical adjuvant, carrier or excipient. Such adjuvants, carriersand/or excipients include, but are not limited to, sterile liquids, suchas water and oils, with or without the addition of a surfactant andother pharmaceutically and physiologically acceptable components.Illustrative oils are those of petroleum, animal, vegetable, orsynthetic origin, for example, peanut oil, soybean oil, or mineral oil.In general, water, saline, aqueous dextrose and related sugar solution,and glycols, such as propylene glycol or polyethylene glycol, arepreferred liquid carriers, particularly for injectable solutions.

These active compounds may also be administered parenterally. Solutionsor suspensions of these active compounds can be prepared in watersuitably mixed with a surfactant such as hydroxypropylcellulose.Dispersions can also be prepared in glycerol, liquid polyethyleneglycols, and mixtures thereof in oils. Illustrative oils are those ofpetroleum, animal, vegetable, or synthetic origin, for example, peanutoil, soybean oil, or mineral oil. In general, water, saline, aqueousdextrose and related sugar solution, and glycols such as, propyleneglycol or polyethylene glycol, are preferred liquid carriers,particularly for injectable solutions. Under ordinary conditions ofstorage and use, these preparations contain a preservative to preventthe growth of microorganisms.

For use as aerosols, the compounds of the present invention in solutionor suspension may be packaged in a pressurized aerosol containertogether with suitable propellants, for example, hydrocarbon propellantslike propane, butane, or isobutane with conventional adjuvants. Thematerials of the present invention also may be administered in anon-pressurized form such as in a nebulizer or atomizer.

In one embodiment, the compounds of this invention are administered incombination with an anti-cancer agent. In one embodiment, theanti-cancer agent is a monoclonal antibody. In some embodiments, themonoclonal antibodies are used for diagnosis, monitoring, or treatmentof cancer. In one embodiment, monoclonal antibodies react againstspecific antigens on cancer cells. In one embodiment, the monoclonalantibody acts as a cancer cell receptor antagonist. In one embodiment,monoclonal antibodies enhance the patient's immune response. In oneembodiment, monoclonal antibodies act against cell growth factors, thusblocking cancer cell growth. In one embodiment, anti-cancer monoclonalantibodies are conjugated or linked to anti-cancer drugs, radioisotopes,other biologic response modifiers, other toxins, or a combinationthereof. In one embodiment, anti-cancer monoclonal antibodies areconjugated or linked to a compound of this invention as describedhereinabove.

Yet another aspect of the present invention relates to a method oftreating cancer that includes selecting a subject in need of treatmentfor cancer, and administering to the subject a pharmaceuticalcomposition comprising a compound according to the first aspect of thepresent invention and a pharmaceutically acceptable carrier underconditions effective to treat cancer.

When administering the compounds of the present invention, they can beadministered systemically or, alternatively, they can be administereddirectly to a specific site where cancer cells or precancerous cells arepresent. Thus, administering can be accomplished in any manner effectivefor delivering the compounds or the pharmaceutical compositions to thecancer cells or precancerous cells. Exemplary modes of administrationinclude, without limitation, administering the compounds or compositionsorally, topically, transdermally, parenterally, subcutaneously,intravenously, intramuscularly, intraperitoneally, by intranasalinstillation, by intracavitary or intravesical instillation,intraocularly, intraarterially, intralesionally, or by application tomucous membranes, such as, that of the nose, throat, and bronchialtubes.

Biological Activity

The compounds of the present invention are useful in the treatment orprevention of various forms of cancer, particularly prostate cancer,breast cancer, ovarian, skin cancer (e.g., melanoma), lung cancer, coloncancer, leukemia, renal cancer, CNS cancer (e.g., glioma, glioblastoma).Treatment of these different cancers is supported by the Examplesherein. Moreover, based upon their mode of action as tubulin inhibitors,other forms of cancer will likewise be treatable or preventable uponadministration of the compounds or compositions of the present inventionto a patient. Preferred compounds of the present invention areselectively disruptive to cancer cells, causing ablation of cancer cellsbut preferably not normal cells. Significantly, harm to normal cells isminimized because the cancer cells are susceptible to disruption at muchlower concentrations of the compounds of the present invention.

Thus, a further aspect of the present invention relates to a method ofdestroying a cancerous cell that includes: providing a compound of thepresent invention and then contacting a cancerous cell with the compoundunder conditions effective to destroy the contacted cancerous cell.According to various embodiments of destroying the cancerous cells, thecells to be destroyed can be located either in vivo or ex vivo (i.e., inculture).

A still further aspect of the present invention relates to a method oftreating or preventing a cancerous condition that includes: providing acompound of the present invention and then administering an effectiveamount of the compound to a patient in a manner effective to treat orprevent a cancerous condition.

According to one embodiment, the patient to be treated is characterizedby the presence of a precancerous condition, and the administering ofthe compound is effective to prevent development of the precancerouscondition into the cancerous condition. This can occur by destroying theprecancerous cell prior to or concurrent with its further developmentinto a cancerous state.

According to another embodiment, the patient to be treated ischaracterized by the presence of a cancerous condition, and theadministering of the compound is effective either to cause regression ofthe cancerous condition or to inhibit growth of the cancerous condition,i.e., stopping its growth altogether or reducing its rate of growth.This preferably occurs by destroying cancer cells, regardless of theirlocation in the patient body. That is, whether the cancer cells arelocated at a primary tumor site or whether the cancer cells havemetastasized and created secondary tumors within the patient body.

When the compounds or pharmaceutical compositions of the presentinvention are administered to treat or prevent a cancerous condition,the pharmaceutical composition can also contain, or can be administeredin conjunction with, other therapeutic agents or treatment regimenpresently known or hereafter developed for the treatment of varioustypes of cancer. Examples of other therapeutic agents or treatmentregimen include, without limitation, radiation therapy, immunotherapy,chemotherapy, surgical intervention, and combinations thereof.

In one embodiment, the invention provides compounds and compositions,including any embodiment described herein, for use in any of the methodsof this invention. In one embodiment, use of a compound of thisinvention or a composition comprising the same, will have utility ininhibiting, suppressing, enhancing or stimulating a desired response ina subject, as will be understood by one skilled in the art. In anotherembodiment, the compositions may further comprise additional activeingredients, whose activity is useful for the particular application forwhich the compound of this invention is being administered.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the severity, reducing the risk of developing orinhibiting cancer comprising administering a compound of this inventionto a subject suffering from cancer under conditions effective to treatthe cancer.

Drug resistance is the major cause of cancer chemotherapy failure. Onemajor contributor to multidrug resistance is overexpression ofP-glycoprotein (P-gp). This protein is a clinically importanttransporter protein belonging to the ATP-binding cassette family of cellmembrane transporters. It can pump substrates including anticancer drugsout of tumor cells through an ATP-dependent mechanism.

In one embodiment, this invention provides methods for: a) treating,suppressing, reducing the severity, reducing the risk, or inhibitingdrug resistant tumors; b) treating, suppressing, reducing the severity,reducing the risk, or inhibiting metastatic cancer; c) treating,suppressing, reducing the severity, reducing the risk, or inhibitingdrug resistant cancer; d) treating, suppressing, reducing the severity,reducing the risk, or inhibiting a drug resistant cancer wherein thecancer is melanoma; e) treating, suppressing, reducing the severity,reducing the risk, or inhibiting a drug resistant cancer wherein thecancer is prostate cancer; f) treating, suppressing, reducing theseverity, reducing the risk, or inhibiting a drug resistant cancerwherein the cancer is uterine cancer; g) treating, suppressing, reducingthe severity, reducing the risk, or inhibiting a drug resistant cancerwherein the cancer is ovarian cancer; h) treating, suppressing, reducingthe severity, reducing the risk, or inhibiting metastatic melanoma; i)treating, suppressing, reducing the severity, reducing the risk, orinhibiting prostate cancer; j) treating, suppressing, reducing theseverity, reducing the risk, or inhibiting uterine cancer; k) treating,suppressing, reducing the severity, reducing the risk, or inhibitingovarian cancer; l) treating, suppressing, reducing the severity,reducing the risk, or inhibiting lung cancer; m) treating, suppressing,reducing the severity, reducing the risk, or inhibiting colon cancer; n)treating, suppressing, reducing the severity, reducing the risk, orinhibiting leukemia; o) treating, suppressing, reducing the severity,reducing the risk, or inhibiting breast cancer; p) treating,suppressing, reducing the severity, reducing the risk, or inhibitingglioma; and/or q) treating, suppressing, reducing the severity, reducingthe risk, or inhibiting cancer in a subject, wherein the subject hasbeen previously treated with chemotherapy, radiotherapy, or biologicaltherapy; comprising the step of administering to said subject a compoundof this invention and/or an isomer, metabolite, pharmaceuticallyacceptable salt, pharmaceutical product, tautomer, hydrate, N-oxide,polymorph, or crystal of said compound, or any combination thereof.

The compounds of the present invention are useful in the treatment,reducing the severity, reducing the risk, or inhibition of cancer,metastatic cancer, drug resistant tumors, drug resistant cancer andvarious forms of cancer. In a preferred embodiment the cancer isprostate cancer, drug-resistant prostate cancer, breast cancer, ovariancancer, drug-resistant ovarian cancer, uterine cancer, drug-resistantuterine cancer, skin cancer (e.g., melanoma), lung cancer, colon cancer,leukemia, lymphoma, head and neck, pancreatic, esophageal, renal canceror CNS cancer (e.g., glioma, glioblastoma). Treatment of these differentcancers is supported by the Examples herein. Moreover, based upon theirmode of action as tubulin inhibitors, other forms of cancer willlikewise be treatable or preventable upon administration of thecompounds or compositions of the present invention to a patient.Preferred compounds of the present invention are selectively disruptiveto cancer cells, causing ablation of cancer cells but preferably notnormal cells. Significantly, harm to normal cells is minimized becausethe cancer cells are susceptible to disruption at much lowerconcentrations of the compounds of the present invention.

In some embodiments, this invention provides for the use of a compoundas herein described, or its isomer, metabolite, pharmaceuticallyacceptable salt, pharmaceutical product, tautomer, polymorph, crystal,N-oxide, hydrate or any combination thereof, for treating, suppressing,reducing the severity, reducing the risk, or inhibiting cancer in asubject. In another embodiment, the cancer is adrenocortical carcinoma,anal cancer, bladder cancer, brain tumor, brain stem tumor, breastcancer, glioma, cerebellar astrocytoma, cerebral astrocytoma,ependymoma, medulloblastoma, supratentorial primitive neuroectodermal,pineal tumors, hypothalamic glioma, breast cancer, carcinoid tumor,carcinoma, cervical cancer, colon cancer, central nervous system (CNS)cancer, endometrial cancer, esophageal cancer, extrahepatic bile ductcancer, Ewing's family of tumors (Pnet), extracranial germ cell tumor,eye cancer, intraocular melanoma, gallbladder cancer, gastric cancer,germ cell tumor, extragonadal, gestational trophoblastic tumor, head andneck cancer, hypopharyngeal cancer, islet cell carcinoma, laryngealcancer, leukemia, acute lymphoblastic leukemia, oral cavity cancer,liver cancer, lung cancer, non-small cell lung cancer, small cell,lymphoma, AIDS-related lymphoma, central nervous system (primary),lymphoma, cutaneous T-cell, lymphoma, Hodgkin's disease, non-Hodgkin'sdisease, malignant mesothelioma, melanoma, Merkel cell carcinoma,metastic squamous carcinoma, multiple myeloma, plasma cell neoplasms,mycosis fungoides, myelodysplastic syndrome, myeloproliferativedisorders, nasopharyngeal cancer, neuroblastoma, oropharyngeal cancer,osteosarcoma, ovarian cancer, ovarian epithelial cancer, ovarian germcell tumor, ovarian low malignant potential tumor, drug-resistantovarian cancer, pancreatic cancer, exocrine, pancreatic cancer, isletcell carcinoma, paranasal sinus and nasal cavity cancer, parathyroidcancer, penile cancer, pheochromocytoma cancer, pituitary cancer, plasmacell neoplasm, prostate cancer, drug-resistant prostate cancer,rhabdomyosarcoma, rectal cancer, renal cancer, renal cell cancer,salivary gland cancer, Sezary syndrome, skin cancer, cutaneous T-celllymphoma, skin cancer, Kaposi's sarcoma, skin cancer, melanoma, smallintestine cancer, soft tissue sarcoma, soft tissue sarcoma, testicularcancer, thymoma, malignant, thyroid cancer, urethral cancer, uterinecancer, drug-resistant uterine cancer, sarcoma, unusual cancer ofchildhood, vaginal cancer, vulvar cancer, Wilms' tumor, or anycombination thereof. In another embodiment the subject has beenpreviously treated with chemotherapy, radiotherapy or biologicaltherapy.

In some embodiments, this invention provides for the use of a compoundas herein described, or its isomer, metabolite, pharmaceuticallyacceptable salt, pharmaceutical product, tautomer, polymorph, crystal,N-oxide, hydrate or any combination thereof, for treating, suppressing,reducing the severity, reducing the risk, or inhibiting a metastaticcancer in a subject. In another embodiment, the cancer is adrenocorticalcarcinoma, anal cancer, bladder cancer, brain tumor, brain stem tumor,breast cancer, glioma, cerebellar astrocytoma, cerebral astrocytoma,ependymoma, medulloblastoma, supratentorial primitive neuroectodermal,pineal tumors, hypothalamic, carcinoid tumor, carcinoma, cervicalcancer, colon cancer, central nervous system (CNS) cancer, endometrialcancer, esophageal cancer, extrahepatic bile duct cancer, Ewing's familyof tumors (Pnet), extracranial germ cell tumor, eye cancer, intraocularmelanoma, gallbladder cancer, gastric cancer, germ cell tumor,extragonadal, gestational trophoblastic tumor, head and neck cancer,hypopharyngeal cancer, islet cell carcinoma, laryngeal cancer, leukemia,acute lymphoblastic, leukemia, oral cavity cancer, liver cancer, lungcancer, non-small cell lung cancer, small cell, lymphoma, AIDS-relatedlymphoma, central nervous system (primary), lymphoma, cutaneous T-cell,lymphoma, Hodgkin's disease, non-Hodgkin's disease, malignantmesothelioma, melanoma, Merkel cell carcinoma, metastic squamouscarcinoma, multiple myeloma, plasma cell neoplasms, mycosis fungoides,myelodysplastic syndrome, myeloproliferative disorders, nasopharyngealcancer, neuroblastoma, oropharyngeal cancer, osteosarcoma, ovariancancer, ovarian epithelial cancer, ovarian germ cell tumor, ovarian lowmalignant potential tumor, drug-resistant ovarian cancer, pancreaticcancer, exocrine, pancreatic cancer, islet cell carcinoma, paranasalsinus and nasal cavity cancer, parathyroid cancer, penile cancer,pheochromocytoma cancer, pituitary cancer, plasma cell neoplasm,prostate cancer, drug-resistant prostate cancer, rhabdomyosarcoma,rectal cancer, renal cancer, renal cell cancer, salivary gland cancer,Sezary syndrome, skin cancer, cutaneous T-cell lymphoma, skin cancer,Kaposi's sarcoma, skin cancer, melanoma, small intestine cancer, softtissue sarcoma, soft tissue sarcoma, testicular cancer, thymoma,malignant, thyroid cancer, urethral cancer, uterine cancer,drug-resistant uterine cancer, sarcoma, unusual cancer of childhood,vaginal cancer, vulvar cancer, Wilms' tumor, or any combination thereof.

In some embodiments, this invention provides for the use of a compoundas herein described, or its isomer, metabolite, pharmaceuticallyacceptable salt, pharmaceutical product, tautomer, polymorph, crystal,N-oxide, hydrate or any combination thereof, for treating, suppressing,reducing the severity, reducing the risk, or inhibiting a drug-resistantcancer or resistant cancer in a subject. In another embodiment, thecancer is adrenocortical carcinoma, anal cancer, bladder cancer, braintumor, brain stem tumor, breast cancer, glioma, cerebellar astrocytoma,cerebral astrocytoma, ependymoma, medulloblastoma, supratentorialprimitive neuroectodermal, pineal tumors, hypothalamic glioma, breastcancer, carcinoid tumor, carcinoma, cervical cancer, colon cancer,central nervous system (CNS) cancer, endometrial cancer, esophagealcancer, extrahepatic bile duct cancer, Ewing's family of tumors (Pnet),extracranial germ cell tumor, eye cancer, intraocular melanoma,gallbladder cancer, gastric cancer, germ cell tumor, extragonadal,gestational trophoblastic tumor, head and neck cancer, hypopharyngealcancer, islet cell carcinoma, laryngeal cancer, leukemia, acutelymphoblastic, leukemia, oral cavity cancer, liver cancer, lung cancer,non-small cell lung cancer, small cell, lymphoma, AIDS-related lymphoma,central nervous system (primary), lymphoma, cutaneous T-cell, lymphoma,Hodgkin's disease, non-Hodgkin's disease, malignant mesothelioma,melanoma, Merkel cell carcinoma, metastic squamous carcinoma, multiplemyeloma, plasma cell neoplasms, mycosis fungoides, myelodysplasticsyndrome, myeloproliferative disorders, nasopharyngeal cancer,neuroblastoma, oropharyngeal cancer, osteosarcoma, ovarian cancer,ovarian epithelial cancer, ovarian germ cell tumor, ovarian lowmalignant potential tumor, pancreatic cancer, exocrine, pancreaticcancer, islet cell carcinoma, paranasal sinus and nasal cavity cancer,parathyroid cancer, penile cancer, pheochromocytoma cancer, pituitarycancer, plasma cell neoplasm, prostate cancer, rhabdomyosarcoma, rectalcancer, renal cancer, renal cell cancer, salivary gland cancer, Sezarysyndrome, skin cancer, cutaneous T-cell lymphoma, skin cancer, Kaposi'ssarcoma, skin cancer, melanoma, small intestine cancer, soft tissuesarcoma, soft tissue sarcoma, testicular cancer, thymoma, malignant,thyroid cancer, urethral cancer, uterine cancer, sarcoma, unusual cancerof childhood, vaginal cancer, vulvar cancer, Wilms' tumor, or anycombination thereof.

In one embodiment “metastatic cancer” refers to a cancer that spread(metastasized) from its original site to another area of the body.Virtually all cancers have the potential to spread. Whether metastasesdevelop depends on the complex interaction of many tumor cell factors,including the type of cancer, the degree of maturity (differentiation)of the tumor cells, the location and how long the cancer has beenpresent, as well as other incompletely understood factors. Metastasesspread in three ways—by local extension from the tumor to thesurrounding tissues, through the bloodstream to distant sites or throughthe lymphatic system to neighboring or distant lymph nodes. Each kind ofcancer may have a typical route of spread. The tumor is called by theprimary site (ex. breast cancer that has spread to the brain is calledmetastatic breast cancer to the brain).

In one embodiment “drug-resistant cancer” refers to cancer cells thatacquire resistance to chemotherapy. Cancer cells can acquire resistanceto chemotherapy by a range of mechanisms, including the mutation oroverexpression of the drug target, inactivation of the drug, orelimination of the drug from the cell. Tumors that recur after aninitial response to chemotherapy may be resistant to multiple drugs(they are multidrug resistant). In the conventional view of drugresistance, one or several cells in the tumor population acquire geneticchanges that confer drug resistance. Accordingly, the reasons for drugresistance, inter alia, are: a) some of the cells that are not killed bythe chemotherapy mutate (change) and become resistant to the drug. Oncethey multiply, there may be more resistant cells than cells that aresensitive to the chemotherapy; b) Gene amplification. A cancer cell mayproduce hundreds of copies of a particular gene. This gene triggers anoverproduction of protein that renders the anticancer drug ineffective;c) cancer cells may pump the drug out of the cell as fast as it is goingin using a molecule called p-glycoprotein; d) cancer cells may stoptaking in the drugs because the protein that transports the drug acrossthe cell wall stops working; e) the cancer cells may learn how to repairthe DNA breaks caused by some anti-cancer drugs; f) cancer cells maydevelop a mechanism that inactivates the drug. One major contributor tomultidrug resistance is overexpression of P-glycoprotein (P-gp). Thisprotein is a clinically important transporter protein belonging to theATP-binding cassette family of cell membrane transporters. It can pumpsubstrates including anticancer drugs out of tumor cells through anATP-dependent mechanism. Thus, the resistance to anticancer agents usedin chemotherapy is the main cause of treatment failure in malignantdisorders, provoking tumors to become resistant. Drug resistance is themajor cause of cancer chemotherapy failure.

In one embodiment “resistant cancer” refers to drug-resistant cancer asdescribed herein above. In another embodiment “resistant cancer” refersto cancer cells that acquire resistance to any treatment such aschemotherapy, radiotherapy or biological therapy.

In one embodiment, this invention is directed to treating, suppressing,reducing the severity, reducing the risk, or inhibiting cancer in asubject, wherein the subject has been previously treated withchemotherapy, radiotherapy or biological therapy.

In one embodiment “Chemotherapy” refers to chemical treatment for cancersuch as drugs that kill cancer cells directly. Such drugs are referredas “anti-cancer” drugs or “antineoplastics.” Today's therapy uses morethan 100 drugs to treat cancer. To cure a specific cancer. Chemotherapyis used to control tumor growth when cure is not possible; to shrinktumors before surgery or radiation therapy; to relieve symptoms (such aspain); and to destroy microscopic cancer cells that may be present afterthe known tumor is removed by surgery (called adjuvant therapy).Adjuvant therapy is given to prevent a possible cancer reoccurrence.

In one embodiment, “Radiotherapy” refers to high energy x-rays andsimilar rays (such as electrons) to treat disease. Many people withcancer will have radiotherapy as part of their treatment. This can begiven either as external radiotherapy from outside the body using x-raysor from within the body as internal radiotherapy. Radiotherapy works bydestroying the cancer cells in the treated area. Although normal cellscan also be damaged by the radiotherapy, they can usually repairthemselves. Radiotherapy treatment can cure some cancers and can alsoreduce the chance of a cancer coming back after surgery. It may be usedto reduce cancer symptoms.

In one embodiment “Biological therapy” refers to substances that occurnaturally in the body to destroy cancer cells. There are several typesof treatment including: monoclonal antibodies, cancer growth inhibitors,vaccines and gene therapy. Biological therapy is also known asimmunotherapy.

In one embodiment, this invention provides a method of treating asubject suffering from prostate cancer, metastatic prostate cancer,resistant prostate cancer or drug-resistant prostate cancer comprisingthe step of administering to said subject a compound of this invention,or its isomer, metabolite, pharmaceutically acceptable salt,pharmaceutical product, tautomer, hydrate, N-oxide, polymorph, crystalor any combination thereof, or a composition comprising the same in anamount effective to treat prostate cancer in the subject. In oneembodiment, the compound is a compound of formula XI, XI(e), XXI, XXIa,XXII, or 17ya. In another embodiment, the compound is compound 17ya. Inone embodiment, the compound is compound 17yab. In another embodiment,the compound is compound 32. In another embodiment, the compound iscompound 31. In yet another embodiment, the compound is compound 31a.

In one embodiment, this invention provides a method for suppressing,reducing the severity, reducing the risk, delaying the progression, orinhibiting prostate cancer, metastatic prostate cancer, resistantprostate cancer or drug-resistant prostate cancer in a subject,comprising administering to the subject a compound of this inventionand/or its isomer, metabolite, pharmaceutically acceptable salt,pharmaceutical product, tautomer, hydrate, N-oxide, polymorph, crystalor any combination thereof or a composition comprising the same. In oneembodiment, the compound is a compound of formula XI, XI(e), XXI, XXIa,XXII, or 17ya. In another embodiment, the compound is compound 17ya. Inone embodiment, the compound is compound 17yab. In another embodiment,the compound is compound 32. In other embodiment, the compound iscompound 31. In yet another embodiment, the compound is compound 31a.

In one embodiment, this invention provides a method of treating asubject suffering from breast cancer, metastatic breast cancer,resistant breast cancer or drug-resistant breast cancer comprising thestep of administering to said subject a compound of this invention, orits isomer, metabolite, pharmaceutically acceptable salt, pharmaceuticalproduct, tautomer, hydrate, N-oxide, polymorph, crystal or anycombination thereof, or a composition comprising the same. In anotherembodiment, the subject is a male or female. In one embodiment, thecompound is a compound of formula XI, XI(e), XXI, XXIa, XXII, or 17ya.In another embodiment, the compound is compound 17ya. In one embodiment,the compound is compound 17yab. In another embodiment, the compound iscompound 32. In other embodiment, the compound is compound 31. In yetanother embodiment, the compound is compound 31a.

In one embodiment, this invention provides a method of suppressing,reducing the severity, reducing the risk, delaying the progression, orinhibiting breast cancer, metastatic breast cancer, resistant breastcancer or drug-resistant breast cancer in a subject comprising the stepof administering to said subject a compound of this invention or itsisomer, metabolite, pharmaceutically acceptable salt, pharmaceuticalproduct, tautomer, hydrate, N-oxide, polymorph, crystal or anycombination thereof, or a composition comprising the same. In anotherembodiment, the subject is a male or female. In one embodiment, thecompound is a compound of formula XI, XI(e), XXI, XXIa, XXII, or 17ya.In another embodiment, the compound is compound 17ya. In one embodiment,the compound is compound 17yab. In another embodiment, the compound iscompound 32. In other embodiment, the compound is compound 31. In yetanother embodiment, the compound is compound 31a.

In another embodiment, this invention provides for the use of a compoundas herein described, or its isomer, metabolite, pharmaceuticallyacceptable salt, pharmaceutical product, tautomer, hydrate, N-oxide,polymorph, crystal or any combination thereof, for treating,suppressing, reducing the severity, reducing the risk, delaying theprogression, or inhibiting ovarian cancer, metastatic ovarian cancer,resistant ovarian cancer or drug-resistant ovarian cancer in a subject.In one embodiment, the compound is a compound of formula XI, XI(e), XXI,XXIa, XXII, or 17ya. In another embodiment, the compound is compound17ya. In one embodiment, the compound is compound 17yab. In anotherembodiment, the compound is compound 32. In other embodiment, thecompound is compound 31. In yet another embodiment, the compound iscompound 31a.

In one embodiment, this invention provides a method for treating,suppressing, reducing the severity, reducing the risk or inhibitingmelanoma, metastatic melanoma, resistant melanoma or drug-resistantmelanoma in a subject, comprising administering to the subject acompound of this invention and/or its isomer, metabolite,pharmaceutically acceptable salt, pharmaceutical product, tautomer,hydrate, N-oxide, polymorph, crystal or any combination thereof. In oneembodiment, the compound is a compound of formula XI, XI(e), XXI, XXIa,XXII, or 17ya. In another embodiment, the compound is compound 17ya. Inone embodiment, the compound is compound 17yab. In another embodiment,the compound is compound 32. In other embodiment, the compound iscompound 31. In yet another embodiment, the compound is compound 31a.

In another embodiment, this invention provides for the use of a compoundas herein described, or isomer, metabolite, pharmaceutically acceptablesalt, pharmaceutical product, tautomer, hydrate, N-oxide, polymorph,crystal or any combination thereof, for treating, suppressing, reducingthe severity, reducing the risk, delaying the progression, or inhibitinglung cancer, metastatic lung cancer, resistant lung cancer ordrug-resistant lung cancer. In one embodiment, the compound is acompound of formula XI, XI(e), XXI, XXIa, XXII, or 17ya. In anotherembodiment, the compound is compound 17ya. In one embodiment, thecompound is compound 17yab. In another embodiment, the compound iscompound 32. In other embodiment, the compound is compound 31. In yetanother embodiment, the compound is compound 31a.

In another embodiment, this invention provides for the use of a compoundas herein described, or isomer, metabolite, pharmaceutically acceptablesalt, pharmaceutical product, tautomer, hydrate, N-oxide, polymorph,crystal any combination thereof, for treating, suppressing, reducing theseverity, reducing the risk, delaying the progression, or inhibitingnon-small cell lung cancer, metastatic small cell lung cancer, resistantsmall cell lung cancer or drug-resistant small cell lung cancer. In oneembodiment, the compound is a compound of formula XI, XI(e), XXI, XXIa,XXII, or 17ya. In another embodiment, the compound is compound 17ya. Inone embodiment, the compound is compound 17yab. In another embodiment,the compound is compound 32. In other embodiment, the compound iscompound 31. In yet another embodiment, the compound is compound 31a.

In another embodiment, this invention provides for the use of a compoundas herein described, or isomer, metabolite, pharmaceutically acceptablesalt, pharmaceutical product, tautomer, hydrate, N-oxide, polymorph,crystal any combination thereof, for treating, suppressing, reducing theseverity, reducing the risk, delaying the progression, or inhibitingcolon cancer, metastatic colon cancer, resistant colon cancer ordrug-resistant colon cancer. In one embodiment, the compound is acompound of formula XI, XI(e), XXI, XXIa, XXII, or 17ya. In anotherembodiment, the compound is compound 17ya. In one embodiment, thecompound is compound 17yab. In another embodiment, the compound iscompound 32. In other embodiment, the compound is compound 31. In yetanother embodiment, the compound is compound 31a.

In another embodiment, this invention provides for the use of a compoundas herein described, or isomer, metabolite, pharmaceutically acceptablesalt, pharmaceutical product, tautomer, hydrate, N-oxide, polymorph,crystal any combination thereof, for treating, suppressing, reducing theseverity, reducing the risk, delaying the progression, or inhibiting ofleukemia, metastatic leukemia, resistant leukemia or drug-resistantleukemia. In one embodiment, the compound is a compound of formula XI,XI(e), XXI, XXIa, XXII, or 17ya. In another embodiment, the compound iscompound 17ya. In one embodiment, the compound is compound 17yab. Inanother embodiment, the compound is compound 32. In other embodiment,the compound is compound 31. In yet another embodiment, the compound iscompound 31a.

In another embodiment, this invention provides for the use of a compoundas herein described, or isomer, metabolite, pharmaceutically acceptablesalt, pharmaceutical product, tautomer, hydrate, N-oxide, polymorph,crystal any combination thereof, for treating, suppressing, reducing theseverity, reducing the risk, delaying the progression, or inhibitingglioma, metastatic glioma, resistant glioma or drug-resistant glioma. Inone embodiment, the compound is a compound of formula XI, XI(e), XXI,XXIa, XXII, or 17ya. In another embodiment, the compound is compound17ya. In one embodiment, the compound is compound 17yab. In anotherembodiment, the compound is compound 32. In other embodiment, thecompound is compound 31. In yet another embodiment, the compound iscompound 31a.

In another embodiment, this invention provides for the use of a compoundas herein described, or isomer, metabolite, pharmaceutically acceptablesalt, pharmaceutical product, tautomer, hydrate, N-oxide, polymorph,crystal any combination thereof, for treating, suppressing, reducing theseverity, reducing the risk, delaying the progression, or inhibitinglymphoma, metastatic lymphoma, resistant lymphoma or drug-resistantlymphoma. In one embodiment, the compound is a compound of formula XI,XI(e), XXI, XXIa, XXII, or 17ya. In another embodiment, the compound iscompound 17ya. In one embodiment, the compound is compound 17yab. Inanother embodiment, the compound is compound 32. In other embodiment,the compound is compound 31. In yet another embodiment, the compound iscompound 31a.

In another embodiment, this invention provides for the use of a compoundas herein described, or isomer, metabolite, pharmaceutically acceptablesalt, pharmaceutical product, tautomer, hydrate, N-oxide, polymorph,crystal any combination thereof, for treating, suppressing, reducing theseverity, reducing the risk, delaying the progression, or inhibitinghead and neck cancer, metastatic head and neck cancer, resistant headand neck cancer or drug-resistant head and neck cancer. In oneembodiment, the compound is a compound of formula XI, XI(e), XXI, XXIa,XXII, or 17ya. In another embodiment, the compound is compound 17ya. Inone embodiment, the compound is compound 17yab. In another embodiment,the compound is compound 32. In other embodiment, the compound iscompound 31. In yet another embodiment, the compound is compound 31a.

In another embodiment, this invention provides for the use of a compoundas herein described, or isomer, metabolite, pharmaceutically acceptablesalt, pharmaceutical product, tautomer, hydrate, N-oxide, polymorph,crystal any combination thereof, for treating, suppressing, reducing theseverity, reducing the risk, delaying the progression, or inhibiting ofpancreatic cancer, metastatic pancreatic cancer, resistant pancreaticcancer or drug-resistant pancreatic cancer. In one embodiment, thecompound is a compound of formula XI, XI(e), XXI, XXIa, XXII, or 17ya.In another embodiment, the compound is compound 17ya. In one embodiment,the compound is compound 17yab. In another embodiment, the compound iscompound 32. In other embodiment, the compound is compound 31. In yetanother embodiment, the compound is compound 31a.

In another embodiment, this invention provides for the use of a compoundas herein described, or isomer, metabolite, pharmaceutically acceptablesalt, pharmaceutical product, tautomer, hydrate, N-oxide, polymorph,crystal any combination thereof, for treating, suppressing, reducing theseverity, reducing the risk, delaying the progression, or inhibitingesophageal cancer, metastatic esophageal cancer, resistant esophagealcancer or drug-resistant esophageal cancer. In one embodiment, thecompound is a compound of formula XI, XI(e), XXI, XXIa, XXII, or 17ya.In another embodiment, the compound is compound 17ya. In one embodiment,the compound is compound 17yab. In another embodiment, the compound iscompound 32. In other embodiment, the compound is compound 31. In yetanother embodiment, the compound is compound 31a.

In another embodiment, this invention provides for the use of a compoundas herein described, or isomer, metabolite, pharmaceutically acceptablesalt, pharmaceutical product, tautomer, hydrate, N-oxide, polymorph,crystal any combination thereof, for treating, suppressing, reducing theseverity, reducing the risk, delaying the progression, or inhibitingrenal cancer, metastatic renal cancer, resistant renal cancer ordrug-resistant renal cancer. In one embodiment, the compound is acompound of formula XI, XI(e), XXI, XXIa, XXI, or 17ya. In anotherembodiment, the compound is compound 17ya. In one embodiment, thecompound is compound 17yab. In another embodiment, the compound iscompound 32. In other embodiment, the compound is compound 31. In yetanother embodiment, the compound is compound 31a.

In another embodiment, this invention provides for the use of a compoundas herein described, or isomer, metabolite, pharmaceutically acceptablesalt, pharmaceutical product, tautomer, hydrate, N-oxide, polymorph,crystal any combination thereof, for treating, suppressing, reducing theseverity, reducing the risk, delaying the progression, or inhibiting CNScancer, metastatic CNS cancer, resistant CNS cancer or drug-resistantCNS cancer. In one embodiment, the compound is a compound of formula XI,XI(e), XXI, XXIa, XXII, or 17ya. In another embodiment, the compound iscompound 17ya. In one embodiment, the compound is compound 17yab. Inanother embodiment, the compound is compound 32. In other embodiment,the compound is compound 31. In yet another embodiment, the compound iscompound 31a.

In some embodiments, this invention provides for the use of a compoundas herein described, or its isomer, metabolite, pharmaceuticallyacceptable salt, pharmaceutical product, tautomer, polymorph, crystal,N-oxide, hydrate or any combination thereof, for treating, suppressing,reducing the severity, reducing the risk, or inhibiting a drug resistantcancerous tumor or tumors in a subject. In another embodiment, thecancer is adrenocortical carcinoma, anal cancer, bladder cancer, braintumor, brain stem tumor, breast cancer, glioma, cerebellar astrocytoma,cerebral astrocytoma, ependymoma, medulloblastoma, supratentorialprimitive neuroectodermal, pineal tumors, hypothalamic glioma, breastcancer, carcinoid tumor, carcinoma, cervical cancer, colon cancer,central nervous system (CNS) cancer, endometrial cancer, esophagealcancer, extrahepatic bile duct cancer, Ewing's family of tumors (Pnet),extracranial germ cell tumor, eye cancer, intraocular melanoma,gallbladder cancer, gastric cancer, germ cell tumor, extragonadal,gestational trophoblastic tumor, head and neck cancer, hypopharyngealcancer, islet cell carcinoma, laryngeal cancer, leukemia, acutelymphoblastic, leukemia, oral cavity cancer, liver cancer, lung cancer,non-small cell lung cancer, small cell, lymphoma, AIDS-related lymphoma,central nervous system (primary), lymphoma, cutaneous T-cell, lymphoma,Hodgkin's disease, non-Hodgkin's disease, malignant mesothelioma,melanoma, Merkel cell carcinoma, metastic squamous carcinoma, multiplemyeloma, plasma cell neoplasms, mycosis fungoides, myelodysplasticsyndrome, myeloproliferative disorders, nasopharyngeal cancer,neuroblastoma, oropharyngeal cancer, osteosarcoma, ovarian cancer,ovarian epithelial cancer, ovarian germ cell tumor, ovarian lowmalignant potential tumor, pancreatic cancer, exocrine, pancreaticcancer, islet cell carcinoma, paranasal sinus and nasal cavity cancer,parathyroid cancer, penile cancer, pheochromocytoma cancer, pituitarycancer, plasma cell neoplasm, prostate cancer, rhabdomyosarcoma, rectalcancer, renal cancer, renal cell cancer, salivary gland cancer, Sezarysyndrome, skin cancer, cutaneous T-cell lymphoma, skin cancer, Kaposi'ssarcoma, skin cancer, melanoma, small intestine cancer, soft tissuesarcoma, soft tissue sarcoma, testicular cancer, thymoma, malignant,thyroid cancer, urethral cancer, uterine cancer, sarcoma, unusual cancerof childhood, vaginal cancer, vulvar cancer, Wilms' tumor, or anycombination thereof. In one embodiment, the compound is a compound offormula XI, XI(e), XXI, XXIa, XXII, or 17ya. In another embodiment, thecompound is compound 17ya. In one embodiment, the compound is compound17yab. In another embodiment, the compound is compound 32. In otherembodiment, the compound is compound 31. In yet another embodiment, thecompound is compound 31a.

In another embodiment, the tumor is prostate cancer tumor. In anotherembodiment, the tumor is a multidrug resistant (MDR) prostate cancertumor. In another embodiment, the tumor is ovarian cancer tumor. In yetanother embodiment, the tumor is a multidrug (MDR) resistant ovariancancer tumor. In another embodiment, the tumor is uterine cancer tumor.In yet another embodiment, the tumor is a multidrug (MDR) resistantuterine cancer tumor. In another embodiment, the tumor is a melanomatumor. In another embodiment, the tumor is a multidrug resistant (MDR)melanoma tumor. In another embodiment, the tumor is a lung cancer tumor.In still another embodiment, the tumor is a colon cancer tumor. Inanother embodiment, the tumor is a breast cancer tumor. In anotherembodiment, the tumor is a glioma tumor. In another embodiment, thetumor is a leukemia tumor.

In one embodiment, this invention is directed to a method of destroyinga cancerous cell comprising: providing a compound of this invention andcontacting the cancerous cell with the compound under conditionseffective to destroy the contacted cancerous cell. According to variousembodiments of destroying the cancerous cells, the cells to be destroyedcan be located either in vivo or ex vivo (i.e., in culture). In oneembodiment, the compound is a compound of formula XI, XI(e), XXI, XXIa,XXII, or 17ya. In another embodiment, the compound is compound 17ya. Inone embodiment, the compound is compound 17yab. In another embodiment,the compound is compound 32. In other embodiment, the compound iscompound 31. In yet another embodiment, the compound is compound 31a.

In another embodiment, the cancer is selected from the group consistingof prostate cancer, drug-resistant prostate cancer, breast cancer,drug-resistant breast cancer, ovarian cancer, drug-resistant ovariancancer, skin cancer, melanoma, lung cancer, colon cancer, leukemia,glioma, renal cancer, CNS cancer, uterine cancer, drug-resistant uterinecancer, and combinations thereof.

In one embodiment, this invention is directed to a method of inhibiting,preventing, or slowing the progress of vascularization of a tumorcomprising administering a compound of this invention to a subjecthaving cancer under conditions effective to inhibit, prevent or slow theprogress of vascularization of said tumor. In one embodiment, thecompound is a compound of formula XI, XI(e), XXI, XXIa, XXII, or 17ya.In another embodiment, the compound is compound 17ya. In one embodiment,the compound is compound 17yab. In another embodiment, the compound iscompound 32. In other embodiment, the compound is compound 31. In yetanother embodiment, the compound is compound 31a.

In one embodiment, this invention is directed to a method of inhibiting,preventing, or slowing the progress of vascularization of a metastatictumor comprising administering a compound of this invention to a subjecthaving cancer under conditions effective to inhibit, prevent or slow theprogress of vascularization of said tumor. In one embodiment, thecompound is a compound of formula XI, XI(e), XXI, XXIa, XXII, or 17ya.In another embodiment, the compound is compound 17ya. In one embodiment,the compound is compound 17yab. In another embodiment, the compound iscompound 32. In other embodiment, the compound is compound 31. In yetanother embodiment, the compound is compound 31a.

In another embodiment, the tumor is selected from the group consistingof prostate cancer tumor, drug-resistant prostate cancer tumor, breastcancer tumor, glioma tumor, ovarian cancer tumor, drug-resistant ovariancancer tumor, skin cancer tumor, melanoma tumor, lung cancer tumor,colon cancer tumor, lymphoma tumor, renal cancer tumor, CNS cancertumor, uterine cancer tumor, drug-resistant uterine cancer tumor, andcombinations thereof.

A still further aspect of the present invention relates to a method oftreating or preventing a cancerous condition that includes: providing acompound of the present invention and then administering an effectiveamount of the compound to a patient in a manner effective to treat orprevent a cancerous condition.

According to one embodiment, the patient to be treated is characterizedby the presence of a precancerous condition, and the administering ofthe compound is effective to prevent development of the precancerouscondition into the cancerous condition. This can occur by destroying theprecancerous cell prior to or concurrent with its further developmentinto a cancerous state.

According to another embodiment, the patient to be treated ischaracterized by the presence of a cancerous condition, and theadministering of the compound is effective either to cause regression ofthe cancerous condition or to inhibit growth of the cancerous condition,i.e., stopping its growth altogether or reducing its rate of growth.This preferably occurs by destroying cancer cells, regardless of theirlocation in the patient body. That is, whether the cancer cells arelocated at a primary tumor site or whether the cancer cells havemetastasized and created secondary tumors within the patient body.

As used herein, subject or patient refers to any mammalian patient,including without limitation, humans and other primates, dogs, cats,horses, cows, sheep, pigs, rats, mice, and other rodents. In oneembodiment, the subject is human. In one embodiment, the subject ismale. In another embodiment, the subject is female. In some embodiments,while the methods as described herein may be useful for treating eithermales or females.

When administering the compounds of the present invention, they can beadministered systemically or, alternatively, they can be administereddirectly to a specific site where cancer cells or precancerous cells arepresent. Thus, administering can be accomplished in any manner effectivefor delivering the compounds or the pharmaceutical compositions to thecancer cells or precancerous cells. Exemplary modes of administrationinclude, without limitation, administering the compounds or compositionsorally, topically, transdermally, parenterally, subcutaneously,intravenously, intramuscularly, intraperitoneally, by intranasalinstillation, by intracavitary or intravesical instillation,intraocularly, intraarterially, intralesionally, or by application tomucous membranes, such as, that of the nose, throat, and bronchialtubes.

The compounds of the present invention are useful in the treatment orprevention of various forms of cancer, particularly prostate cancer,drug-resistant prostate cancer, breast cancer, drug resistant breastcancer, ovarian cancer, drug-resistant ovarian cancer, skin cancer(e.g., melanoma), lung cancer, colon cancer, glioma, leukemia, lymphoma,renal cancer, uterine cancer, drug-resistant uterine cancer, and CNScancer (e.g., glioma, glioblastoma). Treatment of these differentcancers is supported by the Examples herein. Moreover, based upon theirmode of action as tubulin inhibitors, other forms of cancer willlikewise be treatable or preventable upon administration of thecompounds or compositions of the present invention to a patient.Preferred compounds of the present invention are selectively disruptiveto cancer cells, causing ablation of cancer cells but preferably notnormal cells. Significantly, harm to normal cells is minimized becausethe cancer cells are susceptible to disruption at much lowerconcentrations of the compounds of the present invention.

The compounds of the present invention are useful in the treatment,reducing the severity, reducing the risk, or inhibition of cancer,metastatic cancer, resistant cancer or drug-resistant cancer. In anotherembodiment, the cancer is prostate cancer, breast cancer, ovariancancer, skin cancer (e.g., melanoma), lung cancer, colon cancer, glioma,leukemia, lymphoma, head and neck, pancreatic, esophageal, renal cancer,uterine cancer or CNS cancer, or combinations thereof. Treatment ofthese different cancers is supported by the Examples herein. Moreover,based upon their mode of action as tubulin inhibitors, other forms ofcancer will likewise be treatable or preventable upon administration ofthe compounds or compositions of the present invention to a patient.Preferred compounds of the present invention are selectively disruptiveto cancer cells, causing ablation of cancer cells but preferably notnormal cells. Significantly, harm to normal cells is minimized becausethe cancer cells are susceptible to disruption at much lowerconcentrations of the compounds of the present invention. In oneembodiment, the compound is a compound of formula XI, XI(e), XXI, XXIa,XXII, or 17ya. In another embodiment, the compound is compound 17ya. Inone embodiment, the compound is compound 17yab. In another embodiment,the compound is compound 32. In other embodiment, the compound iscompound 31. In yet another embodiment, the compound is compound 31a.

In one embodiment, the compound is administered in combination with ananti-cancer agent by administering the compounds as herein described,alone or in combination with other agents.

When the compounds or pharmaceutical compositions of the presentinvention are administered to treat, suppress, reduce the severity,reduce the risk, or inhibit a cancerous condition, the pharmaceuticalcomposition can also contain, or can be administered in conjunctionwith, other therapeutic agents or treatment regimen presently known orhereafter developed for the treatment of various types of cancer.Examples of other therapeutic agents or treatment regimen include,without limitation, radiation therapy, immunotherapy, chemotherapy,surgical intervention, and combinations thereof.

The following examples are presented in order to more fully illustratethe embodiments of the invention. They should in no way, however, beconstrued as limiting the broad scope of the invention.

EXAMPLES Materials and Methods:

General:

All reagents were purchased from Sigma-Aldrich Chemical Co., FisherScientific (Pittsburgh, Pa.), AK Scientific (Mountain View, Calif.),Oakwood Products (West Columbia, S.C.), etc. and were used withoutfurther purification. Moisture-sensitive reactions were carried under anargon atmosphere. Routine thin layer chromatography (TLC) was performedon aluminum backed Uniplates. (Analtech, Newark, Del.). Melting pointswere measured with Fisher-Johns melting point apparatus (uncorrected).NMR spectra were obtained on a Bruker ARX 300 (Billerica, Mass.)spectrometer or Varian Inova-500 spectrometer. Chemical shifts arereported as parts per million (ppm) relative to TMS in CDCl₃. Massspectral data was collected on a Bruker ESQUIRE electrospray/ion trapinstrument in positive and negative ion modes. Elemental analyses wereperformed by Atlantic Microlab Inc., (Norcross, Ga.).

Cell Culture and Cytotoxicity Assay of Prostate Cancer, Ovarian Cancer,and Melanoma.

All cell lines were obtained from ATCC (American Type CultureCollection, Manassas, Va., USA) unless otherwise specified, while cellculture supplies were purchased from Cellgro Mediatech (Herndon, Va.,USA). We examined the antiproliferative activity of our anti-tubulincompounds in four human prostate cancer cell lines (LNCaP, DU 145, PC-3,and PPC-1) and two human melanoma cell lines (A375 and WM-164). Humanovarian cell line OVCAR-8 and its resistant cell line thatover-expresses P-gp (NCI/ADR-RES) were used as MDR models. Both ovariancell lines were obtained from National Cancer Institutes (NCI). All celllines were tested and authenticated by either ATCC or NCI. All prostatecancer and ovarian cancer cell lines were cultured in RPMI 1640,supplemented with 10% fetal bovine serum (FBS). Melanoma cells werecultured in DMEM, supplemented with 5% FBS, 1% antibiotic/antimycoticmixture (Sigma-Aldrich, Inc., St. Louis, Mo., USA) and bovine insulin (5μg/mL; Sigma-Aldrich). The cytotoxic potential of the anti-tubulincompounds was evaluated using the sulforhodamine B (SRB) assay after 96h of treatment.

Aqueous Solubility. The solubility of drugs was determined byMultiscreen Solubility Filter Plate (Millipore Corporate, Billerica,Mass.) coupled with LC-MS/MS. Briefly, 198 μL of phosphate bufferedsaline (PBS) buffer (pH 7.4) was loaded into 96-well plate, and 2 μL of10 mM test compounds (in DMSO) was dispensed and mixed with gentleshaking (200-300 rpm) for 1.5 h at RT (N=3). The plate was centrifugedat 800 g for 5 min, and the filtrate was used to determine itsconcentration and solubility of test compound by LC-MS/MS as describedbelow.

Pharmacokinetic Study.

Female Sprague-Dawley rats (n=3 or 4; 254±4 g) were purchased fromHarlan Inc. (Indianapolis, Ind.). Rat thoracic jugular vein catheterswere purchased from Braintree Scientific Inc. (Braintree, Mass.). Onarrival at the animal facility, the animals were acclimated for 3 daysin a temperature-controlled room (20-22° C.) with a 12 h light/darkcycle before any treatment. Compound 1-h was administered intravenously(i.v.) into the jugular vein catheters at a dose of 2.5 mg/kg (inDMSO/PEG300, 2/8), whereas 5-Ha and 5-Hc were dosed at 5 mg/kg (inDMSO/PEG300, 1/9). An equal volume of heparinized saline was injected toreplace the removed blood, and blood samples (250 μL) were collected viathe jugular vein catheters at 10, 20, 30 min, and 1, 2, 4, 8, 12, 24 h.Compounds 1-h, 5-Ha and 5-Hc were given (p.o.) by oral gavage at 10mg/kg (in Tween80/DMSO/H₂O, 2/1/7). All blood samples (250 μL) afteroral administration were collected via the jugular vein catheters at 30,60, 90 min, 120 min, 150 min, 180 min, 210 min, 240 min, and 8, 12, 24h. Heparinized syringes and vials were prepared prior to bloodcollection. Plasma samples were prepared by centrifuging the bloodsamples at 8,000 g for 5 min. All plasma samples were stored immediatelyat −80° C. until analyzed.

Analytes were extracted from 100 μL of plasma with 200 μL ofacetonitrile containing 200 nM the internal standard((3,5-dimethoxyphenyl)(2-phenyl-1H-imidazol-4-yl)methanone). The sampleswere thoroughly mixed, centrifuged, and the organic extract wastransferred to autosampler for LC-MS/MS analysis. Multiple reactionmonitoring (MRM) mode, scanning m/z 356→188 (compound 1-h), m/z 371→203(compound 5-Ha), m/z 389→221 (compound 5-Hc), and m/z 309→171 (theinternal standard), was used to obtain the most sensitive signals. Thepharmacokinetic parameters were determined using non-compartmentalanalysis (WinNonlin, Pharsight Corporation, Mountain View, Calif.).

Analytical Method.

Sample solution (10 μL) was injected into an Agilent series HPLC system(Agilent 1100 Series Agilent 1100 Chemstation, Agilent Technology Co,Ltd). All analytes were separated on a narrow-bore C18 column (AlltechAlltima HP, 2.1×100 mm, 3 μm, Fisher, Fair Lawn, N.J.). Two gradientmodes were used. Gradient mode was used to achieve the separation ofanalytes using mixtures of mobile phase A [ACN/H₂O (5%/95%, v/v)containing 0.1% formic acid] and mobile phase B [ACN/H₂O (95%/5%, v/v)containing 0.1% formic acid] at a flow rate of 300 μL/min. Mobile phaseA was used at 15% from 0 to 1 min followed by a linearly programmedgradient to 100% of mobile phase B within 6 min, 100% of mobile phase Bwas maintained for 0.5 min before a quick ramp to 15% mobile phase A.Mobile phase A was continued for another 12 min towards the end ofanalysis.

In Vitro Tubulin Polymerization Assay.

Bovine brain tubulin (0.4 mg, >97% pure) (Cytoskeleton, Denver, Colo.)was mixed with 10 μM of the test compounds and incubated in 100 μL ofgeneral tubulin buffer (80 mM PIPES, 2.0 mM MgCl₂, 0.5 mM EGTA, and 1 mMGTP) at pH 6.9. The absorbance of wavelength at 340 nm was monitoredevery 1 min for 20 min by the SYNERGY 4 Microplate Reader (Bio-TekInstruments, Winooski, Vt.). The spectrophotometer was set at 37° C. fortubulin polymerization.

A triple-quadruple mass spectrometer, API Qtrap 4000™ (AppliedBiosystems/MDS SCIEX, Concord, Ontario, Canada), operating with aTurbolonSpray source was used. The spraying needle voltage was set at 5kV for positive mode. Curtain gas was set at 10; Gas 1 and gas 2 wereset 50. Collision-Assisted-Dissociation (CAD) gas at medium and thesource heater probe temperature at 500° C. Data acquisition andquantitative processing were accomplished using Analyst™ software, Ver.1.4.1 (Applied Biosystems).

The purity of the final compounds was tested via RP-HPLC on a Waters2695 HPLC system installed with a Photodiode Array Detector. Two RP-HPLCmethods were conducted using a Supelco Ascentis™ 5 μM C-18 column(250×4.6 mm) at ambient temperature, and a flow rate of 0.7 mL/min.HPLC1: Gradient: Solvent A (water) and Solvent B (methanol): 0-20 min40-100% B (linear gradient), 20-27 min 100% B. HPLC2: Gradient: SolventA (water) and Solvent B (methanol): 0-15 min 40-100% B (lineargradient), 15-25 min 100% B. UV detection at 254 nm.

Example 1: Synthesis of Thiazole, Thiazoline, and ThiazolidineCarboxamides

The synthesis of thiazole and thiazolidine carboxamides is generallydisclosed in U.S. Pat. No. 7,307,093 to Miller et al. and U.S. Pat. No.7,662,842 to Miller et al., each of which is hereby incorporated byreference in its entirety. The synthesis of various thiazole,dihydrothiazole, and thiazolidine carboxamides of the present inventionis also illustrated in Scheme 1 below.

General Procedure for the Preparation of (2RS,4R)-2-aryl-thiazolidine-4-carboxylic acid 1.

A mixture of L-cysteine (3.16 g, 26.11 mmol) and appropriate aldehyde(26.15 mmol) in ethanol (300 mL) and water (30 mL) was stirred at roomtemperature for 6-15 h, and the solid that precipitated out wascollected, washed with diethyl ether, and dried to afford the according(2RS, 4R)-2-aryl-thiazolidine-4-carboxylic acid 1 with yields of 70-99%.At 0° C., 1 (5.95 mmol) was dissolved in 1 N NaOH (6 mL) and 1,4-dioxane(15 mL), then di-tert-butyldicarbonate (2.80 g, 12.80 mmol) was addedslowly and stirred at room temperature for 1 h. The reaction mixture wasconcentrated in vacuum and washed with ethyl acetate (20 mL). Theaqueous phase was adjusted to pH=4 by adding 1 N HCl or 5% KHSO₄, thenextracted with ethyl acetate, dried with magnesium sulfate, filtered andconcentrated on vacuum to give corresponding BOC protected acids aswhite foam-solids, which were used for next step without furtherpurification.

General Procedure for the Preparation of(2RS,4R)-2-Aryl-N-(3,4,5-trimethoxyphenyl)thiazolidine-4-carboxamides2a,2b

A mixture of appropriate BOC protected carboxylic acids (0.3-0.5 g),EDCI (1.2 equiv) and HOBT (1.05 equiv) in CH₂Cl₂ (20 mL) was stirred atroom temperature for 10 min. To this solution, 3,4,5-trimethoxyaniline(1.05 equiv) and Et₃N (1.2 equiv) were added and stirring continued atroom temperature (RT or r.t.) for 6-8 h. The reaction mixture wasdiluted with CH₂Cl₂ (30 mL) and sequentially washed with water, satd.NaHCO₃, brine and dried over MgSO₄. The solvent was removed underreduced pressure to yield a crude oil, which were stirred with TFA(0.6-1 mL) in 20 mL CH₂Cl₂ at RT for 1-8 h to cleave the BOC group. Thereaction mixture was concentrated, washed with satd. NaHCO₃ and driedover MgSO₄. The solvent was removed to yield a crude solid, andcompounds 2a-2b were purified by column chromatography. Yield wasreported as 2 steps yield.

(2RS,4R)-2-Phenyl-N-(3,4,5-trimethoxyphenyl)thiazolidine-4-carboxamide(Compound 2a)

Yield: 69.5%. M. p. 158-159° C. ¹H NMR (300 MHz, CDCl₃) δ 9.14 (s,0.8H), 8.61 (s, 0.2H), 7.58-7.32 (m, 5H), 6.90 (s, 1.6H), 6.71 (s,0.4H), 5.71 (dd, 0.2H, J=9.0 Hz), 5.42 (dd, 0.8H, J=11.7 Hz), 4.53 (dt,0.8H), 4.19 (m, 0.2H), 3.87, 3.80 (s, s, 6H), 3.82, 3.78 (s, s, 3H),3.80-3.78 (m, 0.4H), 3.62-3.42 (m, 1.6H), 2.96 (t, 0.2H, J=9.0 Hz), 2.74(dd, 0.8H, J=11.7 Hz). MS (ESI) m/z 375.1 [M+H]⁺, 397.1 [M+Na]⁺. Anal.(C₁₉H₂₂N₂O₄S) C, H, N.

(2RS,4R)—N,2-bis(3,4,5-trimethoxyphenyl)thiazolidine-4-carboxamide(Compound 2b)

Yield: 34.5%. M. p. 147-149° C. ¹H NMR (300 MHz, CDCl₃) δ 9.10 (s,0.7H), 8.59 (s, 0.3H), 6.90 (s, 1.4H), 6.80 (s, 0.6H), 6.74 (s, 1.4H),6.71 (s, 0.6H), 5.66 (br, 0.3H), 5.35 (d, br, 0.7H, J=7.5 Hz), 4.52 (br,0.7H), 4.21 (br, 0.3H), 3.90, 3.87, 3.86, 3.84, 3.82, 3.81, 3.79, 3.78(all s, 18H), 3.66-3.61, 3.54-3.38 (m, 1.6H), 2.98, 2.72 (br, 1H). MS(ESI) m/z 465.1 [M+H]⁺, 487.1 [M+Na]⁺. Anal. (C₂₂H₂₈N₂O₇S) C, H, N.

To enhance the activity and to develop more selective agents, thissynthesis was extended and, as discussed in the subsequent examples,biological studies were performed to examine the nature of thesubstituents attached to the carbonyl at the 4 position. The synthesisof these additional compounds is shown in Scheme 2 below.

Synthesis of2-Phenyl-N-(3,4,5-trimethoxyphenyl)-4,5-dihydrothiazole-4-carboxamides4a-4b, 5

Unsubstituted (or substituted) benzonitrile (40 mmol) was combined withL- or D-cysteine (45 mmol) in 100 mL of 1:1 MeOH/pH6.4 phosphate buffersolution. The reaction was stirred at 40° C. for 3 days (Bergeron etal., “Evaluation of Desferrithiocin and its Synthetic Analogs as OrallyEffective Iron Chelators,” J. Med. Chem. 34:2072-8 (1991), which ishereby incorporated by reference in its entirety). Precipitate wasremoved through filtration, and MeOH was removed using rotaryevaporation. To the remaining solution was added 1 M HCl to adjust pH=4under 0° C. The resulting precipitate was extracted into CH₂Cl₂, driedand concentrated (Scheme 2). The carboxylic acids 3a,3b were reactedwith 3,4,5-trimethoxyaniline using the same procedures as described forpreparation of compounds 2a,2b, thereby forming compounds 4a,4b.Conversion of the dihydrothiazoles 4a,4b to the thiazolidine 5 wascarried out by oxidation with BrCCl₃/DBU (Williams et al., “Studies ofMild Dehydrogenations in Heterocyclic Systems,” Tetrahedron Lett.38:331-334 (1997), which is hereby incorporated by reference in itsentirety).

(4R)-2-Phenyl-4,5-dihydrothiazole-4-carboxylic acid (Compound 3a)

Yield: 58.3%. ¹H NMR (300 MHz, CDCl₃) δ 9.31 (br, 1H), 7.88-7.85 (m,2H), 7.55-7.41 (m, 3H), 5.38 (t, 1H, J=9.6 Hz), 3.75 (dt, 2H, J=9.6 Hz,2.7 Hz). MS (ESI) m/z 162.0 [M−COOH]⁻.

(4S)-2-Phenyl-4,5-dihydrothiazole-4-carboxylic acid (Compound 3b)

Yield: 53.9%. ¹H NMR (300 MHz, CDCl₃) δ 7.89-7.85 (m, 2H), 7.55-7.41 (m,3H), 5.38 (t, 1H, J=9.3 Hz), 3.75 (dt, 2H, J=9.3 Hz, 2.7 Hz). MS (ESI)m/z 162.0 [M−COOH]⁻.

(4R)-2-Phenyl-N-(3,4,5-trimethoxyphenyl)-4,5-dihydrothiazole-4-carboxamide(Compound 4a)

Yield: 98.7%. M. p. 121-122° C. ¹H NMR (300 MHz, CDCl₃) δ 8.98 (s, 1H),8.02-7.94, 7.62-7.48 (m, 5H), 6.93 (s, 2H), 5.38 (t, 1H, J=9.6 Hz),3.92-3.85 (m, 2H), 3.87 (s, 6H), 3.82 (s, 3H). MS (ESI) m/z 373.1[M+H]⁺. Anal. (C₁₉H₂₀N₂O₄S) C, H, N.

(4R)-2-Phenyl-N-(3,4,5-trimethoxyphenyl)-4,5-dihydrothiazole-4-carboxamide(Compound 4b)

Yield: 70.7%. M. p. 122-123° C. ¹H NMR (300 MHz, CDCl₃) δ 8.62 (s, 1H),7.93-7.90 (m, 2H), 7.55-7.45 (m, 3H), 6.88 (s, 2H), 5.31 (t, 1H, J=9.6Hz), 3.86 (s, 6H), 3.79 (s, 3H), 3.83-3.70 (m, 2H). MS (ESI) m/z 395.1[M+Na]⁺, 370.9 [M−1]⁻. Anal. (C₁₉H₂₀N₂O₄S) C, H, N.

2-Phenyl-N-(3,4,5-trimethoxyphenyl)thiazole-4-carboxamide (Compound 5)

Yield: 89.7%. M. p. 157-158° C. ¹H NMR (300 MHz, CDCl₃) δ 9.30 (s, 1H),8.20 (s, 1H), 8.04-8.01 (m, 2H), 7.53-7.51 (m, 3H), 7.08 (s, 2H), 3.92(s, 6H), 3.86 (s, 3H). MS (ESI) m/z 393.1 [M+Na]⁺. Anal. (C₁₉H₁₈N₂O₄S)C, H, N.

Example 2: Synthesis of Thiazole and Thiazolidine Methanone Derivatives2-(Substituted-phenyl)-4,5-dihydrothiazole-4-carboxylic acidmethoxymethylamide Intermediates

As shown in Scheme 3 below, 2-(substituted-phenyl)- and unsubstituted2-phenyl-4,5-dihydrothiazole-4-carboxylic acids 3 were prepared fromappropriate nitriles (e.g., benzonitrile, pyridinyl-nitrile,pyrimidinyl-nitrile, thiophene-yl-nitrile) and L-cysteine as describedabove. The obtained carboxylic acids were then used for the synthesis ofthe methoxymethylamide intermediates. A mixture of appropriate theappropriate carboxylic acid 3 (5 mmol), EDCI (6 mmol) and HOBt (5 mmol)in CH₂Cl₂ (50 mL) was stirred for 10 min. To this solution, NMM (5 mmol)and HNCH₃OCH₃ (5 mmol) was added and stirring continued at roomtemperature for 6-8 hours. The reaction mixture was diluted with CH₂Cl₂(100 mL) and sequentially washed with water, Satd. NaHCO₃, brine anddried over MgSO₄. The solvent was removed under reduced pressure toyield a crude product 6, which was purified by column chromatography.

(R)—N-Methoxy-N-methyl-2-phenyl-4,5-dihydrothiazole-4-carboxamide(Compound 6a)

Yield: 92.0%. ¹H NMR (300 MHz, CDCl₃) δ 7.85-7.83 (m, 2H), 7.48-7.36 (m,3H), 5.66 (t, 1H, J=9.0 Hz), 3.90 (s, 3H), 3.88-3.80 (br, 1H), 3.55-3.47(dd, 1H, J=10.8 Hz, 9.0 Hz), 3.30 (s, 3H). MS (ESI) m/z 251.0 [M+H]⁻,273.0 [M+Na]⁺.

(R)—N-Methoxy-N-methyl-2-p-tolyl-4,5-dihydrothiazole-4-carboxamide(Compound 6b)

Yield: 55.8%. ¹H NMR (300 MHz, CDCl₃) δ 7.79 (d, 2H, J=7.8 Hz), 7.22 (d,2H, J=7.8 Hz), 5.68 (t, 1H, J=8.7 Hz), 3.91 (s, 3H), 3.80 (t, 1H, J=9.3Hz), 3.55 (t, 1H, J=9.3 Hz), 3.30 (s, 3H), 2.93 (s, 3H). MS (ESI) m/z265.0 [M+H]⁺, 287.0 [M+Na]⁺.

(R)-2-(2-Fluorophenyl)-N-methoxy-N-methyl-4,5-dihydrothiazole-4-carboxamide(Compound 6c)

Yield: 39.6%. ¹H NMR (300 MHz, CDCl₃) δ 7.91 (dt, 1H, J=7.5 Hz, 1.8 Hz),7.43 (m, 1H), 7.19-7.09 (m, 2H), 5.63 (t, 1H), 3.88 (s, 3H), 3.83 (br,1H), 3.48 (dd, 1H, J=11.1 Hz, 9.6 Hz), 3.30 (s, 3H). MS (ESI) m/z 291.0[M+Na]⁺.

(R)-2-(3-Fluorophenyl)-N-methoxy-N-methyl-4,5-dihydrothiazole-4-carboxamide(Compound 6d)

Yield: 84.3%. ¹H NMR (300 MHz, CDCl₃) δ 7.60-7.56 (m, 2H), 7.38 (dt, 1H,J=8.1 Hz, 6.0 Hz), 7.16 (dt, 1H, J=8.1 Hz, 2.4 Hz), 5.67 (t, 1H), 3.90(s, 3H), 3.86-3.83 (br, 1H), 3.52 (dd, 1H, J=10.8 Hz, 9.3 Hz), 3.30 (s,3H). MS (ESI) m/z 291.0 [M+Na]⁺.

(R)-2-(4-Fluorophenyl)-N-methoxy-N-methyl-4,5-dihydrothiazole-4-carboxamide(Compound 6e)

Yield: 66.0%. ¹H NMR (300 MHz, CDCl₃) δ 7.90 (d, 2H), 7.13 (d, 2H), 5.63(t, 1H), 3.88 (s, 3H), 3.83 (br, 1H), 3.46 (dd, 1H), 3.31 (s, 3H). MS(ESI) m/z 269.0 [M+H]⁺.

(R)-2-(3,4-Dimethoxyphenyl)-N-methoxy-N-methyl-4,5-dihydrothiazole-4-carboxamide(Compound 6f)

Yield: 36.7%. ¹H NMR (300 MHz, CDCl₃) δ 8.11 (d, 1H), 7.93 (s, 1H),7.19-7.09 (d, 1H), 5.41 (t, 1H), 3.97 (s, 6H), 3.89 (s, 3H), 3.73 (br,1H), 3.39 (dd, 1H), 3.31 (s, 3H). MS (ESI) m/z 333.1 [M+Na]⁺.

(R)—N-Methoxy-N-methyl-2-(4-nitrophenyl)-4,5-dihydrothiazole-4-carboxamide(Compound 6g)

Yield: 53.7%. ¹H NMR (300 MHz, CDCl₃) δ 8.25 (d, 2H, J=9.0 Hz), 8.01 (d,2H, J=9.0 Hz), 5.73 (t, 1H), 3.90 (s, 3H), 3.87 (br, 1H), 3.59 (dd, 1H,J=11.1 Hz, 9.3 Hz), 3.31 (s, 3H). MS (ESI) m/z 318.1 [M+Na]⁺.

(R)-2-(4-Cyanophenyl)-N-methoxy-N-methyl-4,5-dihydrothiazole-4-carboxamide(Compound 6h)

Yield: 26.7%. ¹H NMR (300 MHz, CDCl₃) δ 7.94 (d, 2H, J=8.1 Hz), 7.69 (d,2H, J=8.1 Hz), 5.71 (t, 1H, J=9.3 Hz), 3.89 (s, 3H), 3.87 (br, 1H), 3.56(dd, 1H, J=10.8 Hz, 9.3 Hz), 3.30 (s, 3H). MS (ESI) m/z 298.0 [M+Na]⁺.

(R)—N-Methoxy-N-methyl-2-(4-trifluoromethylphenyl)-4,5-dihydrothiazole-4-carboxamide(Compound 6i)

Yield: 62.0%. ¹H NMR (300 MHz, CDCl₃) δ 7.95 (d, 2H, J=8.1 Hz), 7.65 (d,2H, J=8.1 Hz), 5.70 (t, 1H, J=9.6 Hz), 3.89 (s, 3H), 3.85 (br, 1H), 3.55(dd, 1H, J=10.8 Hz, 9.6 Hz), 3.30 (s, 3H). MS (ESI) m/z 341.0 [M+Na]⁺.

(R)-2-(4-Bromophenyl)-N-methoxy-N-methyl-4,5-dihydrothiazole-4-carboxamide(Compound 6j)

Yield: 20.0%. ¹H NMR (300 MHz, CDCl₃) δ 7.71, 7.53 (d, d, 4H, J=8.4 Hz),5.63 (t, 1H, J=9.6 Hz), 3.88 (s, 3H), 3.84 (t, 1H, J=9.6 Hz), 3.52 (dd,1H, J=10.8 Hz, 9.6 Hz), 3.30 (s, 3H). MS (ESI) m/z 351.0 [M+Na]⁺.

(R)—N-Methoxy-N-methyl-2-(4-ethylphenyl)-4,5-dihydrothiazole-4-carboxamide(Compound 6k)

Yield: 77.7%. ¹H NMR (300 MHz, CDCl₃) δ 7.75 (d, 2H, J=8.4 Hz), 7.21 (d,2H, J=8.4 Hz), 5.64 (t, 1H), 3.89 (s, 3H), 3.81 (m, 1H), 3.48 (dd, 1H,J=10.8 Hz, 9.3 Hz), 3.29 (s, 3H), 2.67 (q, 2H), 1.24 (t, 3H). MS (ESI)m/z 301.0 [M+Na]⁺.

(R)—N-Methoxy-N-methyl-2-(pyridin-4-yl)-4,5-dihydrothiazole-4-carboxamide(Compound 6l)

Yield: 66.6%. ¹H NMR (300 MHz, CDCl₃) δ 8.70 (d, 2H, J=9.0 Hz), 7.67 (d,2H, J=9.0 Hz), 5.71 (t, 1H, J=9.6 Hz), 3.90 (s, 3H), 3.73 (t, 1H), 3.55(dd, 1H, J=10.8 Hz, 9.6 Hz), 3.30 (s, 3H). MS (ESI) m/z 252.1 [M+H]⁺,274.0 [M+Na]⁺.

(R)—N-Methoxy-N-methyl-2-(pyrimidin-2-yl)-4,5-dihydrothiazole-4-carboxamide(Compound 6m)

Yield: 32.5%. ¹H NMR (300 MHz, CDCl₃) δ 8.88 (d, 2H, J=4.8 Hz), 7.38 (t,1H, J=4.8 Hz), 5.83 (t, 1H, J=9.0 Hz), 3.87 (s, 3H), 3.56 (dd, 2H, J=9.0Hz), 3.30 (s, 3H). MS (ESI) m/z 275.0 [M+Na]⁺.

(R)—N-Methoxy-N-methyl-2-(thiophen-2-yl)-4,5-dihydrothiazole-4-carboxamide(Compound 6p)

Yield: 58.5%. ¹H NMR (300 MHz, CDCl₃) δ 7.57 (br, 1H), 7.49 (d, 1H,J=4.8 Hz), 7.09 (dd, 1H, J=3.6 Hz, 4.8 Hz), 5.64 (t, 1H, J=9.0 Hz), 3.90(s, 3H), 3.85 (br, 1H), 3.57 (dd, 1H, J=9.9 Hz, 9.0 Hz), 3.29 (s, 3H).MS (ESI) m/z 279.0 [M+Na]⁺.

N-Methoxy-N-methylthiazole-4-carboxamide (Compound 9a)

Yield: 58.7%. ¹H NMR (300 MHz, CDCl₃) δ 8.82 (d, 1H, J=2.1 Hz), 8.10 (d,1H, J=2.1 Hz), 3.79 (s, 3H), 3.45 (s, 3H). MS (ESI) m/z 194.9 [M+Na]⁺.

2-(Substituted-phenyl)-thiazole-4-carboxylic acid methoxymethylamides7a-p

A solution of the resulting dihydrothiazole-4-carboxylic acidmethoxymethylamides 6a-6p (1 equiv) in CH₂Cl₂ was cooled to 0° C.,distilled, and DBU (2 equiv) was added. Bromotrichloromethane (1.7equiv) was then introduced dropwise via syringe over 10 min. Thereaction mixtures were allowed to warm to room temperature and stirredovernight. Upon washing with satd. aqueous NH₄Cl (2×50 mL), the aqueousphase was extracted with EtOAc (3×50 mL). The combined organic layerswere dried on MgSO₄, filtered and concentrated in vacuo. The residue waspurified by flash chromatography as needed providing compounds 7a-p.

2-Phenyl-thiazole-4-carboxylic acid methoxymethylamide (Compound 7a)

Yield: 73.6%. ¹H NMR (300 MHz, CDCl₃) δ 8.01 (s, 1H), 7.99-7.96 (m, 2H),7.47-7.44 (m, 3H), 3.88 (s, 3H), 3.49 (s, 3H). MS (ESI) m/z 271.0[M+Na]⁺.

(2-(Substituted-phenyl)-thiazol-4-yl)-(substituted-phenyl)-methanones

As shown in Scheme 3 above, three different methods were utilized forthe synthesis of the methanones 8a-8z.

Method 1:

To a solution of n-BuLi (1.6 M, 0.713 mL) in 8 mL THF was added asolution of 3,4,5-trimethoxybromobenzene (1.09 mmol) in 3 mL THF under−78° C. The mixture was stirred for 2 h and a solution of amides 6 or 7(1.14 mmol) in 3 mL THF was charged. The mixture was allowed to warm toroom temperature and stirred overnight. The reaction mixture wasquenched with satd. NH₄Cl, extracted with ethyl ether, dried with MgSO₄,and exposed in air atmosphere overnight. The solvent was removed underreduced pressure to yield a crude product, which was purified by columnchromatography to obtain pure compounds 8a-8z.

Method 2:

To a solution of corresponding Grignard reagents (0.5 M, 3 mL) in 2 mLTHF was charged a solution of amides 6 or 7 (1 mmol) in 3 mL THF at 0°C. The mixtures were stirred for 30 min to 2 hours until amidesdisappeared on TLC plates. The reaction mixture was quenched with satd.NH₄Cl, extracted with ethyl ether, dried with MgSO₄ and to set in airatmosphere overnight to yield 6 as starting material. The solvent wasremoved under reduced pressure to yield a crude product, which waspurified by column chromatography to obtain pure compound 8a-8z.

Hydrochloride salts of compounds 8i, 8x, and 8w were also prepared. At0° C., to a solution of 10 mL HCl in ethyl ether (2 M) solution wasadded 8i, 8x or 8w (100 mg) in 5 mL CH₂Cl₂ (5 mL) and stirred overnight.The hydrochloride precipitate was filtered and washed with ethyl ether.Drying under high vacuum yielded the corresponding salts.

Phenyl (2-phenylthiazol-4-yl)-methanone (Compound 8a)

Yield: 76.3%. M. p. 65-66° C. ¹H NMR (300 MHz, CDCl₃) δ 8.32-8.29 (m,2H), 8.24 (s, 1H), 8.04-8.00 (m, 2H), 7.64-7.52 (m, 3H), 7.50-7.46 (m,3H). MS (ESI) m/z 288.0 [M+Na]⁺. Anal. (C₁₆H₁₁NOS) C, H, N.

(4-Methoxyphenyl)(2-phenylthiazol-4-yl)-methanone (Compound 8b)

Yield: 74.8%. M. p. 105-106° C. ¹H NMR (300 MHz, CDCl₃) δ 8.41 (d, 2H),8.22 (s, 1H), 8.02 (dd, 2H), 7.47 (m, 3H), 7.01 (d, 2H), 3.80 (s, 3H).MS (ESI) m/z 318.1 [M+Na]⁺. Anal. (C₁₇H₁₃NO₂S) C, H, N.

(3-Methoxyphenyl)(2-phenylthiazol-4-yl)-methanone (Compound 8c)

Yield: 58.8%. M. p. 43-44° C. ¹H NMR (300 MHz, CDCl₃) δ 8.23 (s, 1H),8.05-8.01 (m, 2H), 7.93 (d, 1H), 7.84 (m, 1H), 7.49-7.40 (m, 4H),7.16-7.15 (m, 1H), 3.89 (s, 3H). MS (ESI) m/z 318.1 [M+Na]⁺. Anal.(C₁₇H₁₃NO₂S) C, H, N.

(2-Methoxyphenyl)(2-phenylthiazol-4-yl)-methanone (Compound 8d)

Yield: 57.4%. Colorless oil. ¹H NMR (300 MHz, CDCl₃) δ 8.03 (s, 1H),7.98-7.95 (m, 2H), 7.57-7.47 (m, 2H), 7.47-7.42 (m, 3H), 7.08-7.01 (m,2H), 3.78 (s, 3H). MS (ESI) m/z 318.1 [M+Na]⁺. Anal. (C₁₇H₁₃NO₂S) C, H,N.

(3,4-Dimethoxyphenyl)(2-phenylthiazol-4-yl)-methanone (Compound 8e)

Yield: 15.3%. M. p. 89-91° C. ¹H NMR (500 MHz, CDCl₃) δ 8.24 (s, 1H),8.22 (dd, 1H, J=8.5 Hz, 2.0 Hz), 8.04-8.02 (m, 2H), 7.99 (d, 1H, J=2.0Hz), 7.49-7.47 (m, 3H), 6.98 (d, 1H, J=8.5 Hz), 3.99 (s, 6H). MS (ESI)m/z 348.0 [M+Na]⁺. Anal. (C₁₈H₁₅NO₃S) C, H, N.

(2-Phenyl-thiazol-4-yl)-(3,4,5-trimethoxy-phenyl)-methanone (Compound8f)

Yield: 27.3%. M. p. 133-135° C. ¹H NMR (300 MHz, CDCl₃) δ 8.29 (s, 1H),8.03 (q, 2H), 7.80 (s, 2 H), 7.49-7.47 (m, 3H), 3.96 (s, 6H), 3.97 (s,3H). MS (ESI) m/z 378.1 [M+Na]⁺. Anal. (C₁₉H₁₇NO₄S) C, H, N.

(3,5-Dimethoxyphenyl)(2-phenylthiazol-4-yl)-methanone (Compound 8g)

Yield: 41.5%. M. p. 84-85° C. ¹H NMR (300 MHz, CDCl₃) δ 8.23 (s, 1H),8.04-8.01 (m, 2H), 7.99 (d, 2H, J=2.4 Hz), 7.49-7.43 (m, 3H), 6.72 (t,1H, J=2.4 Hz), 3.87 (s, 6H). MS (ESI) m/z 348.3 [M+Na]⁺. Anal.(C₁₈H₁₅NO₃S) C, H, N.

(2-Fluorophenyl)(2-phenylthiazol-4-yl)-methanone (Compound 8h)

Yield: 66.4%. M. p. 77-79° C. ¹H NMR (300 MHz, CDCl₃) δ 8.48-8.41 (m,2H), 8.28 (s, 2H), 8.04-7.98 (m, 2H), 7.50-7.46 (m, 3H), 7.26-7.16 (m,2H). MS (ESI) m/z 306.0 [M+Na]⁺, 283.9 [M−H]⁻. Anal. (C₁₆H₁₀FNOS) C, H,N.

(2-Phenylthiazol-4-yl)-(pyridin-2-yl)-methanone (Compound 8i)

Yield: 20.7%. M. p. 95-97° C. ¹H NMR (300 MHz, CDCl₃) δ 9.01 (s, 1H),8.77 (d, 1H, J=4.8 Hz), 8.28 (d, 1H, J=7.8 Hz), 8.08-8.05 (m, 2H), 7.92(dt, 1H, J=7.8 Hz, 1.2 Hz), 7.52 (ddd, 1H, J=7.8 Hz, 4.8 Hz, 1.2 Hz),7.48-7.46 (m, 3H). (compound 8i.HCl salt): Yield: 70.6%. M. p. 105-107°C. ¹H NMR (300 MHz, DMSO-d₆) δ 9.03 (s, 1H), 8.79 (d, 1H, J=4.8 Hz),8.10 (br, 1H), 8.08 (br, 1H), 8.03-8.00 (m, 2H), 7.73-7.69 (m, 1H),7.56-7.54 (m, 3H). MS (ESI) m/z 267.0 [M+H]⁺. Anal. (C₁₅H₁₀N₂OS,C₁₅H₁₀N₂OS.HCl) C, H, N.

1-(2-Phenylthiazol-4-yl)-heptadecan-1-one (Compound 8j)

Yield: 66.4%. M. p. 63-64° C. ¹H NMR (300 MHz, CDCl₃) δ 8.12 (s, 1H),8.02-7.99 (m, 2H), 7.49-7.47 (m, 3H), 3.16 (t, 2H, J=7.5 Hz), 1.82-1.72(m, 2H), 1.26 (s, 26H), 0.88 (t, 3H, J=6.9 Hz). MS (ESI) m/z 414.4[M+H]⁺. Anal. (C₂₆H₃₉NOS) C, H, N.

(2-p-Tolylthiazol-4-yl)-(3,4,5-trimethoxyphenyl)-methanone (Compound 8k)

Yield: 53.2%. M. p. 116-119° C. ¹H NMR (300 MHz, CDCl₃) δ 8.25 (s, 1H),7.91 (d, 2H, J=8.1 Hz), 7.80 (s, 2H), 7.28 (d, 2H, J=8.1 Hz), 3.96 (s,3H), 3.95 (s, 6H). MS (ESI) m/z 392.1 [M+Na]⁺. Anal. (C₂₀H₁₉NO₄S) C, H,N.

[2-(2-Fluorophenyl)-thiazol-4-yl]-(3,4,5-trimethoxyphenyl)-methanone(Compound 8l)

Yield: 39.6%. M. p. 90-102° C. ¹H NMR (500 MHz, CDCl₃) δ 8.40 (s, 1H),8.33 (dt, 1H, J=1.5 Hz, 8.0 Hz), 7.78 (s, 2H), 7.49-7.44 (m, 1H),7.30-7.23 (m, 2H), 3.97 (s, 3H), 3.95 (s, 6H). MS (ESI) m/z 396.1[M+Na]⁺. Anal. (C₁₉H₁₆FNO₄S) C, H, N.

[2-(3-Fluorophenyl)-thiazol-4-yl](3,4,5-trimethoxyphenyl)-methanone(Compound 8m)

Yield: 14.1%. M. p. 122-124° C. ¹H NMR (300 MHz, CDCl₃) δ 8.31 (s, 1H),7.79 (s, 2H), 7.76-7.74 (m, 2H), 7.45 (dt, 1H, J=6.0 Hz, 8.4 Hz), 7.18(dt, 1H, J=1.8 Hz, 8.4 Hz), 3.97 (s, 3H), 3.96 (s, 6H). MS (ESI) m/z396.1 [M+Na]⁺. Anal. (C₁₉H₁₆FNO₄S) C, H, N.

[2-(4-Fluorophenyl)-thiazol-4-yl]-(3,4,5-trimethoxyphenyl)-methanone(Compound 8n)

Yield: 40.2%. M. p. 153-155° C. ¹H NMR (300 MHz, CDCl₃) δ 8.27 (s, 1H),8.04-8.00 (dd, 2H, J=8.4 Hz, 5.7 Hz), 7.75 (s, 2H), 7.21-7.15 (t, 3H,J=8.4 Hz), 3.97 (s, 3H), 3.95 (s, 6H). MS (ESI) m/z 396.1 [M+Na]⁺. Anal.(C₁₉H₁₆FNO₄S) C, H, N.

[2-(3,4-Dimethoxyphenyl)-thiazol-4-yl]-(3,4,5-trimethoxyphenyl)-methanone(Compound 8o)

Yield: 46.6%. M. p. 145-147° C. ¹H NMR (300 MHz, CDCl₃) δ 8.20 (s, 1H),7.76 (s, 2H), 7.58-7.54 (m, 2H), 6.94 (d, 2H, J=8.1 Hz), 3.96 (s, 6H),3.95 (s, s, 9H). MS (ESI) m/z 438.1 [M+Na]⁺. Anal. (C₂₁H₂₁NO₆S.¼H₂O) C,H, N.

[2-(4-Nitrophenyl)-thiazol-4-yl]-(3,4,5-trimethoxyphenyl)-methanone(Compound 8p)

Yield: 46.4%. M. p. 199-200° C. ¹H NMR (300 MHz, CDCl₃) δ 8.38 (d, 2H,J=8.7 Hz), 8.34 (s, 1H), 8.20 (d, 2H, J=8.7 Hz), 7.73 (s, 2H), 3.98 (s,3H), 3.95 (s, 6H). MS (ESI) m/z 423.1 [M+Na]⁺. Anal. (C₁₉H₁₆N₂O₆S) C, H,N.

4-[4-(3,4,5-Trimethoxybenzoyl)-thiazol-2-yl]-benzonitrile (Compound 8q)

Yield: 45.9%. M. p. 181-182° C. ¹H NMR (300 MHz, CDCl₃) δ 8.37 (s, 1H),8.13 (d, 2H, J=8.4 Hz), 7.78 (d, 2H, J=8.4 Hz), 7.72 (s, 2H), 3.97 (s,3H), 3.94 (s, 6H). MS (ESI) m/z 403.1 [M+Na]⁺. Anal. (C₂₀H₁₆N₂O₄S) C, H,N.

4-[4-(3,4,5-Trimethoxybenzoyl)-thiazol-2-yl]-benzoic acid (Compound 8r)

Yield: 61.9%. M. p.>220° C. (dec.). ¹H NMR (300 MHz, CDCl₃) δ 8.65 (s,1H), 8.00 (d, d, 4H), 7.65 (s, 2H), 3.88 (s, 6H), 3.80 (s, 3H). MS (ESI)m/z 397.9 [M−H]⁻, 353.9 [M−COOH]⁻. Anal. (C₂₀H₁₇NO₆S) C, H, N.

Methyl-4-[4-(3,4,5-trimethoxybenzoyl)-thiazol-2-yl]-benzoate (Compound8s)

Yield: 72.5%. M. p. 172-174° C. ¹H NMR (300 MHz, CDCl₃) δ 8.35 (s, 1H),8.12 (dd, 4H, J=8.4 Hz), 7.78 (s, 2H), 3.97 (s, 3H), 3.96 (s, 3H), 3.95(s, 6H). MS (ESI) m/z 436.1 [M+Na]⁺. Anal. (C₂₁H₁₉NO₆S) C, H, N.

(2-(4-(Trifluoromethyl)-phenyl)-thiazol-4-yl)(3,4,5-trimethoxyphenyl)-methanone(Compound 8t)

Yield: 45.5%. M. p. 144-145° C. ¹H NMR (300 MHz, CDCl₃) δ 8.35 (s, 1H),8.14, 7.65 (d, d, 4H, J=8.1 Hz), 7.76 (s, 2H), 3.97 (s, 3H), 3.95 (s,6H). MS (ESI) m/z 446.1 [M+Na]⁺. Anal. (C₂₀H₁₆F₃NO₄S) C, H, N.

[2-(4-Bromophenyl)-thiazol-4-yl]-(3,4,5-trimethoxyphenyl)-methanone(Compound 8u)

Yield: 51.8%. M. p. 149-150° C. ¹H NMR (300 MHz, CDCl₃) δ 8.28 (s, 1H),7.89, 7.62 (d, d, 4H, J=8.1 Hz), 7.75 (s, 2H), 3.97 (s, 3H), 3.94 (s,6H). MS (ESI) m/z 456.0, 458.0 [M+Na]⁺. Anal. (C₁₉H₁₆BrNO₄S) C, H, N.

[2-(4-Ethyl-phenyl)-thiazol-4-yl]-(3,4,5-trimethoxy-phenyl)-methanone(Compound 8v)

Yield: 40.0%. M. p. 86-87° C. ¹H NMR (300 MHz, CDCl₃) δ 8.25 (s, 1H),7.93, 7.31 (d, d, 4H, J=8.4 Hz), 7.81 (s, 2H), 3.97 (s, 3H), 3.95 (s,6H). MS (ESI) m/z 406.1 [M+Na]⁺. Anal. (C₂₁H₂₁NO₄S) C, H, N.

[2-(4-Amino-phenyl)-thiazol-4-yl]-(3,4,5-trimethoxy-phenyl)-methanone(Compound 8w)

Yield: 61.8%. M. p. 177-179° C. ¹H NMR (300 MHz, CDCl₃) δ 8.14 (s, 1H),7.82, 7.65 (d, d, 4H, J=8.4 Hz), 7.78 (s, 2H), 3.96 (s, 3H), 3.94 (s,6H). (compound 8w.HCl salt): Yield: 50.1%. M. p. 166-169° C. ¹H NMR (300MHz, DMSO-d₆) δ 8.49 (s, 1H), 7.84, 6.94 (d, d, 4H, J=8.4 Hz), 7.62 (s,2H), 3.86 (s, 3H), 3.79 (s, 6H). MS (ESI) m/z 393.1 [M+Na]⁺. Anal.(C₁₉H₁₈N₂O₄S, C₁₉H₁₈N₂O₄S.HCl) C, H, N.

[2-(Pyridin-4-yl)-thiazol-4-yl]-(3,4,5-trimethoxyphenyl)-methanone(Compound 8x)

Yield: 29.3%. M. p. 178-180° C. ¹H NMR (300 MHz, CDCl₃) δ 8.77 (dd, 2H,J=6.0 Hz, 1.5 Hz), 8.40 (s, 1H), 7.87 (dd, 2H, J=6.0 Hz, 1.8 Hz), 7.75(s, 2H), 3.98 (s, 3H), 3.95 (s, 6H). (compound 8x.HCl salt): Yield:92.7%. M. p. 182-184° C. ¹H NMR (300 MHz, CDCl₃) δ 8.85 (br, 2H), 8.52(s, 1H), 8.22 (br, 2H), 7.66 (s, 2H), 3.98 (s, 3H), 3.94 (s, 6H). MS(ESI) m/z 379.1 [M+Na]⁺. Anal. (C₁₈H₁₆N₂O₄S, C₁₈H₁₆N₂O₄S.HCl) C, H, N.

[2-(Pyrimidin-2-yl)-thiazol-4-yl]-(3,4,5-trimethoxyphenyl)-methanone(Compound 8y)

Yield: 51.9%. M. p. 190-191° C. ¹H NMR (300 MHz, CDCl₃) δ 8.88 (d, 2H,J=4.8 Hz), 8.44 (s, 1H), 7.73 (s, 2H), 7.37 (t, 1H, J=4.8 Hz), 3.95 (s,3H), 3.94 (s, 6H). MS (ESI) m/z 380.1 [M+Na]⁺. Anal. (C₁₇H₁₅N₃O₄S) C, H,N.

[2-(Thiophen-2-yl)-thiazol-4-yl]-(3,4,5-trimethoxyphenyl)-methanone(Compound 8z)

Yield: 30.5%. M. p. 111-113° C. ¹H NMR (300 MHz, CDCl₃) δ 8.25 (s, 1H),7.90 (s, 2H), 7.58 (dd, 1H, J=3.6, 0.9 Hz), 7.46 (dd, 1H, J=5.4, 0.9Hz), 7.12 (dd, 1H, J=5.4, 3.6 Hz), 3.98 (s, 6H), 3.97 (s, 3H). MS (ESI)m/z 384.1 [M+Na]⁺. Anal. (C₁₇H₁₅NO₄S₂) C, H, N.

Thiazol-4-yl-(3,4,5-trimethoxy-phenyl)-methanone (Compound 10a)

Yield: 49.4%. M. p. 106-108° C. ¹H NMR (300 MHz, CDCl₃) δ 8.92 (d, 1H,J=2.1 Hz), 8.34 (d, 1H, J=2.1 Hz), 7.61 (s, 2H), 3.94 (s, 3H), 3.93 (s,6H). MS (ESI) m/z 302.0 [M+Na]⁺. Anal. (C₁₃H₁₃NO₄S) C, H, N.

Method 3:

(2-Phenyl-thiazol-4-yl)-(3,4,5-trihydroxy-phenyl)-methanone (11f) wassynthesized beginning with compound 8f. To a solution of compound 8f(123 mg, 0.35 mmol) in 5 mL anh. CH₂Cl₂ was added BBr₃ (1 M solution inCH₂Cl₂, 1.75 mL, 5 mmol) under −78° C. The mixture was stirred for 2 hand a solution of amide 7 (1.14 mmol) in 3 mL THF was charged. Themixture was allowed to warm to room temperature slowly and stirredovernight. The reaction mixture was quenched with satd. NH₄Cl, extractedwith ethyl acetate, dried with MgSO₄. The solvent was removed underreduced pressure to yield a crude product, which was purified by columnchromatography to obtain pure compound as red crystalline solid. Yield:50.9%. M. p. 175-176° C. ¹H NMR (300 MHz, DMSO-d₆) δ 8.44 (d, 1H),8.07-8.04 (m, 2H), 7.57-7.55 (m, 3H), 7.33 (s, 2H). MS (ESI) m/z 336.1[M+Na]⁺. Anal. (C₁₆H₁₁NO₄S) C, H, N.

Example 3: X-Ray Crystallography Structure Determination for Compound 8f

Compound 8f was recrystallized from hexane and ethyl acetate, and singlecolorless crystals suitable for X-ray diffraction were obtained. X-raycrystallographic data for 8f were collected from a single crystalmounted with paratone oil on a nylon cryoloop. Data were collected at100K on a Bruker Proteum CCD area detector, controlled by Proteum2software (Proteum2, Bruker AXS Inc., Madison, Wis., USA (2005)), using arotating-anode generator and Osmic mirrors to generate Cu radiation(λ=1.54178 Å). The data were reduced using SAINT (SAINT, Bruker AXSInc., Madison, Wis., USA. (1998)), with an absorption correction appliedusing SADABS (SADABS, Bruker AXS Inc., Madison, Wis., USA. (2000)) basedon redundant reflections; this correction included a sphericalcomponent. The structure was solved using direct methods (SHELXS^(x4)),which revealed all of the heavy atoms. Structure refinement with SHELXL(SHELXL-97, G. M. Sheldrick, University of Göttingen, Germany (1997))was carried out using full-matrix methods based on F², and proceededsmoothly. Hydrogen atoms were added to the structural model assumingideal C—H distances and isotropic ADPs constrained to be similar to thatof the bonded carbon atom. In the final model, anisotropic ADPs wererefined for all heavy atoms, and isotropic ADPs for chemically-similarhydrogens (e.g. methyl H) were constrained to be identical. The finalrefinement parameters are: wR2=0.084 for 228 parameters and 3066independent observations, R1=0.031, S (goodness-of-fit)=1.057.

An ORTEP drawing of 8f with the atom labeling scheme is shown in FIG. 1.The X-ray structure showed that 8f molecule contained a conjugatedsystem composed of three aromatic rings and a carbonyl group linkerbetween “B” and “C” ring as expected (“A” ring=phenyl; “B”ring=thiazole; “C” ring=3,4,5-trimethoxyphenyl). As a result, two C—Cbonds adjacent to C═O and C—C— bond between “A” phenyl and “B” thiazolering display (C1-C7=1.496(2) Å; C7-C8=1.492(2) Å; C10-C11=1.471(2) Å)shorter bond lengths than normal C—C single bond (1.54 Å) and longerthan normal C═C double bond (1.34 Å) (see Table 1 below). Thus,conjugation of the π system is possible for “A”, “B”, “C” rings andcarbonyl group. The carbonyl group is nearly coplanar with the adjacent“B” thiazole ring (O-C7-C1-C6 16.2(2)°, O-C7-C8-C9 9.7(2)°).

TABLE 1 Selected Geometric Parameters of Compound 8f (Å, °) C1—C71.496(2) O—C7—C1 120.1(2) C7—O 1.224(2) C8—C7—C1 121.9(2) C7—C8 1.492(2)C9—C8—N 115.1(2) C8—C9 1.371(2) C9—C8—C7 121.7(2) C8—N 1.380(2) N—C8—C7123.0(2) C9—S 1.711(2) C8—C9—S 110.0(1) S—C10 1.747(2) C9—S—C10 89.6(1)C10—N 1.303(2) N—C10—C11 123.5(2) C10—C11 1.471(2) N—C10—S 113.9(1)C2—C1—C6 121.2(2) C11—C10—S 122.6(1) C2—C1—C7 122.3(2) C10—N—C8 111.4(2)C6—C1—C7 116.4(2) C12—C11—C10 122.3(2) O—C7—C8 118.0(2) C16—C11—C10118.5(2)

Example 4: In Vitro Assays for Anti-Cancer Cytotoxicity

In vitro assays were tested against both melanoma cell lines andprostate cancer cells lines. In each case, standard sulforhodamine Bassay was used. Cells were seeded into 96-well plates at 1000 to 5000cells/well depending on growth rates. After 12 hours, media were changedand serial dilutions of compounds were added. Cells were incubated witheach compound for 48 hours. Fresh media containing the test compoundwere changed ever 24 hours. Thereafter, total cell proteinscorresponding to cell numbers (both viable and non-viable cells) weremeasured using the sulforhodamine B (SRB) assay according tomanufacturer's protocol (Sigma-Aldrich, Inc.) (Rubinstein et al.,“Comparison of in vitro Anticancer Drug-screening Data Generated with aTetrazolium Assay Versus a Protein Assay Against a Diverse Panel ofHuman Tumor Cell Lines,” J. Natl. Cancer Inst. 82:1113-1118 (1990);Dothager et al., “Synthesis and Identification of Small Molecules thatPotently Induce Apoptosis in Melanoma Cells Through G1 Cell CycleArrest,” J. Am. Chem. Soc. 127:8686-8696 (2005), each of which is herebyincorporated by reference in their entirety).

For melanoma assays, one human melanoma cell line (A375) and one mousemelanoma cell line (B16-F1) were used. A375 cells and B16-F1 cells werepurchased from ATCC (American Type Culture Collection, Manassas, Va.,USA). Fibroblast cells were used as a control to determine theselectivity of these compounds against melanoma. Human dermal fibroblastcells were purchased from Cascade Biologics, Inc., Portland, Oreg., USA.All cell lines were cultured in DMEM (Cellgro Mediatech, Inc., Herndon,Va., USA), supplemented with 5% FBS (Cellgro Mediatech), 1%antibiotic/antimycotic mixture (Sigma-Aldrich, Inc., St. Louis, Mo.,USA) and bovine insulin (5 μg/ml; Sigma-Aldrich). Cultures weremaintained at 37° C. in a humidified atmosphere containing 5% CO₂. Cellswere exposed to a wide range of concentrations for 48 h inround-bottomed 96-well plates. Cells were fixed with 10% trichloroaceticacid and washed five times with water. After cells were air-driedovernight and stained with SRB solution, total proteins were measured at560 nm with a plate reader. IC₅₀ (i.e., concentration which inhibitedcell growth by 50% of no treatment controls) values were obtained bynonlinear regression analysis with GraphPad Prism (GraphPad Software,San Diego, Calif.).

For prostate cancer assays, four human prostate cancer cell lines(LNCaP, DU 145, PC-3, and PPC-1) were selected. LNCaP, PC-3 and DU 145cells were purchased from ATCC (American Type Culture Collection,Manassas, Va., USA). Dr. Mitchell Steiner at University of TennesseeHealth Science Center kindly provided PPC-1 cells. All prostate cancercell lines were cultured in RPMI 1640 (Cellgro Mediatech, Inc., Herndon,Va., USA), and supplemented with 10% FBS (Cellgro Mediatech). Cultureswere maintained at 37° C. in a humidified atmosphere containing 5% CO₂.1000 to 5000 cells were plated into each well of 96-well platesdepending on growth rate and exposed to different concentrations of atest compound for 96 h in three to five replicates. Cell numbers at theend of the drug treatment were measured by the SRB assay. Briefly, thecells were fixed with 10% of trichloroacetic acid and stained with 0.4%SRB, and the absorbances at 540 nm were measured using a plate reader(DYNEX Technologies, Chantilly, Va.). Percentages of cell survivalversus drug concentrations were plotted and the IC₅₀ (concentration thatinhibited cell growth by 50% of untreated control) values were obtainedby nonlinear regression analysis using WinNonlin (Pharsight Corporation,Mountain View, Calif.).

The results of these assays are provided in Tables 2-4 below.

Modifications of the “B” ring from a thiazolidine to thiazole system andthe linker from an amide to a ketone. In prior ATCAA compounds, thethiazolidine ring, which contained a free NH at its 3-position, wasshown to be important for cytotoxicity. Once the “B” ring thiazolidinemoiety was replaced by a thiazoline ring, the antiproliferative activitydecreased sharply from 0.6 μM to over 50 μM on WM-164 cell lines (Li etal., “Synthesis and Antiproliferative Activity of Thiazolidine Analogsfor Melanoma,” Bioorg. Med. Chem. Lett. 17:4113-7 (2007), which ishereby incorporated by reference in its entirety). The ATCAA-1 fattyamide derivative that was most effective against melanoma and prostatecancer cell lines were examined and shown to have an IC₅₀ 0.4-2.2 μM(see Table 2). Replacement of the long fatty chain with a certainaromatic bulky substituent such as fluorene (ATCAA-2) showed inhibitoryactivity on both cancer cell lines (IC₅₀=1.6-3.9 μM). The fluorene groupin 4-carboxylic amide position was also replaced by3,4,5-trimethoxylphenyl group (2a and 2b), but the potency against bothcancer cell lines was lost. The subsequent “B” ring modification fromsaturated thiazolidine compound 2a to unsaturated thiazole 5 did notshow any cytotoxicity against either cancer cell line tested. Butthiazoline enantiomers 4a and 4b (R-isomer and S-isomer, with similarantiproliferative activities) showed improved activity (IC₅₀=3.4-38.3μM) compared with 2a, 2b and 5. When the amide CONH linkage between “B”ring and “C” ring was replaced by a carbonyl linker, the mixtures ofthiazoline/thiazole ketone 8f were obtained instead of desiredthiazoline ketone, because the auto-dehydrogenation between thiazolineand thiazole occurred (the conversion was shown in FIG. 2).Surprisingly, introduction of the carbonyl group linker and thiazole “B”ring led to a significant enhancement of growth inhibition of examinedcancer cell lines with a low nanomolar level (8f, IC₅₀=0.021-0.071 μM)that is comparable to the natural anticancer agent colchicine.Consequently, a series of the related compounds with “B” as a thiazolering were designed and synthesized based on the discovery of 8f. Theiranticancer activity was also evaluated against melanoma and prostatecancer.

Modifications of the “C” ring also had significant effects. Variation ofthe phenyl substituents has a remarkable change in effect on potency.The in vitro assay results shown in Table 3 provide interesting results,but only the 3,4,5-trimethoxylphenyl “C” ring (8f) showed excellentinhibition against all cancer cells (IC₅₀=21-71 nM, average IC₅₀=41 nM).Compound 8g, with a 3,5-dimethoxyphenyl group, showed 6-fold averagecytotoxicity lower than 8f against six different cell lines(IC₅₀=170-424 nM, calcd. average IC₅₀=261 nM). Modifications of 8f byremoval of one methoxy at meta-position (8e) or two methoxy groups (8b,8c and 8d) from 8f led to a dramatic loss in activity (IC₅₀>20 μM).Although ortho-substituted monomethoxy compound 8d exhibited weakactivity against a certain cell lines compared with meta-/para-MeOsubstituted 8c/8b and dimethoxyphenyl compound 8e, none of them showedsignificant potency in inhibition compared with 8f. Similar trends werealso seen in 8h and 8j with 2-fluorophenyl and hexadecyl in “C” ringmodifications.

Modifications of the “A” ring using different para-substituted electronwithdrawing groups (EWG) and electron donor groups (EDG) did not showclear influence on antiproliferative activity. Introduction of a weakEWG (4-F in 8n, IC₅₀ values: 6-43 nM) or weak EDG (4-CH₃ in 8k, IC₅₀s:5-21 nM), both increased the potency compared with 8f (see Table 4). Thereplacement of para-position with strong EWG such as NO₂ (Sp), CN (8q),CF₃ (8t) or introducing strong EDG (3,4-dimethoxy) to “A” phenyl ring(8o) exhibited comparable antiproliferative activity.

To compare the effects of ortho-, meta- and para-substitutions, a fluoroatom was introduced to different positions of “A” phenyl ring (8l, 8m,and 8n). The various o-, m-, p-substituents did not exhibit equalactivities. p-Fluoro substituted 8n has the best activity for examinedprostate cancer cells (6-13 nM) while o-fluoro substituted 8l showed thelowest IC₅₀ values (27-30 nM) against melanoma cells. 8n has similaraverage IC₅₀ values (33-43 nM) against melanoma compared with 8l. Buto-fluoro substituted 8l has lowest potency (IC₅₀ values: 52-114 nM)among the three substituted compounds on prostate cancer cells.Meta-substituted compound 8m showed lowest activity on melanoma cells(IC₅₀ values: 287-304 nM) but showed moderate inhibition on prostatecancer cells (IC₅₀ values: 23-46 nM).

Turning to the effects of steric hindrance group on the “A” phenyl ringsubstituents, it was found that p-bromo (8u, IC₅₀ values: 18-44 nM)caused a decrease in antiproliferative activity relative to p-fluoroposition (8n, IC₅₀ values: 6-12 nM) but only against prostate cancercells. Reduced activity against both cancer cell lines occurred whenp-methyl (8k, IC₅₀ values: 5-21 nM) was replaced with a p-ethyl group(8v, IC₅₀ values: 17-70 nM).

To investigate if the phenyl ring played an essential role at the “A”ring site, phenyl at 2-thiazole position was removed and compound 10 wasobtained. This modification caused a total loss of activity comparedwith 8f. The replacement of the “A” ring by pyridine (compound 8x) hadthe same effect. Moreover, substituting 2-pyrimidine in “A” ring(compound 8y) also caused a significant loss of activity (IC₅₀s:11.8-41.0 μM). However, introducing the thiophene replacement of phenyl(8z) into “A” position improved the potency calcd. 1-3 folds on allexamined cell lines (IC₅₀s: 9-38 nM) compared to 8f (IC₅₀s: 21-71 nM).

Because many of the compounds show poor water-solubility, threewater-soluble salts were prepared after introducing a hydrophilic groupsuch as NH₂ (8w) and COOH (8r) into “A” ring to form HCl or sodiumsalts. Another modification is replacing “A”/“C” rings in 8a withpyridine (8i, 8x, 8y) or pyrimidine rings, which could also be convertedinto HCl salts. These modifications reduced the calculated Log P values(Log P=2.74-3.90) compared with 8a and 8f (Log P=4.46 and 4.08).Introducing p-amino to “A” phenyl (8w) is the only case to increase theantiproliferative activity (HCl salt, IC₅₀ values: 11-29 nM) comparedwith 8f against all cell lines. Although replacing phenyl withpyrimidine (8y) kept partial activity against both cancer cells, thepotency range was markedly reduced from nM to μM compared with 8f.Unfortunately, introducing COOH to para-phenyl “A” ring and pyridine to“A” or “C” rings (8i, 8r, 8x) all resulted in the total loss of theanti-cancer activity. A total loss of potency was seen in the methylester 8s of acid 8r against both cancer cell lines. Demethylation ofcompound 8f afforded water soluble 3,4,5-trihydroxyphenyl at “C” ringcompound 1f, but this demethylation results in complete loss ofantiproliferative activity against all tested cancer cells, which alsopoints out the importance of 3,4,5-trimethoxyphenyl at “C” position ofthe methanones.

Given these results, compound 8f was also subjected to in vitro testingin an NCI-60 screening assay, which measures the ability of the compoundto act against six leukemia cell lines, eight non-small cell lung cancercell lines, seven colon cancer cell lines, six CNS cancer (e.g.,glioma/glioblastoma) cell lines, eight melanoma cell lines, six ovariancancer cell lines, seven renal cancer cell lines, two prostate cancercell lines, and eight breast cancer cell lines. The results of theNCI-60 assay showed broad activity against all of these cancers, withGI₅₀ values in the nanomolar range (<1.0×10⁻⁸) against most cell linesand TGI values in the micromolar range against most cell lines. TGIvalues in the nanomolar range were obtained against several leukemiacell lines, one lung cancer cell line, several colon cancer cell lines,several ovarian cancer cell lines, and several breast cancer cell lines.

TABLE 2 In Vitro Inhibitory Effects of Modificated ATCAA Compoundsagainst the Proliferation of Melanoma (A375, B16-F1) and Prostate CancerCells (DU145, PC-3, LNCaP, PPC-1)

IC₅₀ ± SEM (μM) A ring B ring^(a) C ring^(b) X B16-F1 A375 DU 145 PC-3LNCaP PPC-1 ATCAA-1 p- TZD C₁₆H₃₃ CONH 2.2 ± 0.3 2.1 ± 0.2 1.7 ± 0.1 1.2± 0.1 1.0 ± 0.1 0.4 ± 0.1 NHAc—Ph ATCAA-2 p- TZD 9H-fluoren- CONH 3.9 ±0.3 2.1 ± 0.1 1.9 ± 0.3 2.1 ± 0.1 3.5 ± 0.7 1.6 ± 0.1 NHAc—Ph 1-yl 2a PhTZD 3,4,5- CONH >100 >100 >20 >20 >20 >20 triMeO—Ph 2b 3,4,5- TZD 3,4,5-CONH >100 >100 >20 >20 >20 >20 triMeO—Ph triMeO—Ph 4a(4R) Ph TZL 3,4,5-CONH 38.3 ± 3.2  22.8 ± 1.6  >20 >20 >20 5.3 ± 0.3 triMeO—Ph 4b(4S) PhTZL 3,4,5- CONH 30.4 ± 2.8  13.6 ± 1.2  >20 13.2 ± 2.1  16.8 ± 1.8  3.4± 0.2 triMeO—Ph 5 Ph TZ 3,4,5- CONH >100 >100 >20 >20 >20 >20 triMeO—Ph8f Ph TZ 3,4,5- CO 0.055 ± 0.005 0.028 ± 0.005 0.071 ± 0.004 0.021 ±0.001 0.028 ± 0.004 0.043 ± 0.005 triMeO—Ph Colchicine 0.029 ± 0.0050.020 ± 0.003 0.010 ± 0.002 0.011 ± 0.001 0.016 ± 0.004 0.020 ± 0.001^(a). TZD = Thiazolidine, TZL = Thiazoline, TZ = Thiazole; ^(b)ForATCAA-1, “C” position contains a lipid chain. ATCAA-1 and ATCAA-2 wereprepared using appropriate starting materials according to Scheme 1 ofExample 1 (see also Li et al., “Synthesis and Antiproliferative Activityof Thiazolidine Analogs for Melanoma,” Bioorg. Med. Chem. Lett.17:4113-7 (2007); Gududuru et al., “Discovery of 2-Arylthiazolidine-4-Carboxylic Acid Amides as a New Class of CytotoxicAgents for Prostate Cancer,” J. Med. Chem. 48:2584-2588 (2005), each ofwhich is hereby incorporated by reference in its entirety).

TABLE 3 In Vitro Growth Inhibitory Effects of Compounds 8a-8j withDifferent “C” Rings Against Proliferation of Melanoma (A 375, B16-F1)and Prostate Cancer Cells (DU145, PC-3, LNCaP, PPC-1) IC₅₀ ± SEM (μM)Compounds 8 C Ring B16-F1 A375 DU 145 PC-3 LNCaP PPC-1

8a 8b 8c 8d 8e 8f 8g 8h 8j Ph 4-MeO—Ph 3-MeO—Ph 2-MeO—Ph 3,4-diMeO—Ph3,4,5-triMeO—Ph 3,5-diMeO—Ph 2-Fluoro—Ph Hexadecyl^(a) >100 >100 >10059.4 ± 21.2 >100 0.055 ± 0.005 0.350 ± 0.2  >100 18.6 ±17.5 >100 >100 >100 70.3 ± 32.5 >100 0.028 ± 0.005 0.170 ± 0.1  >10016.0 ± 15.2 >20 >20 >20 >20 >20 0.071 ± 0004  0.424 ±0.098 >20 >20 >20 >20 >20 >20 >20 0.021 ± 0.001 0.301 ±0.030 >20 >20 >20 >20 >20 >20 >20 0.028 ± 0.004 0.323 ±0.041 >20 >20 >20 >20 >20 >20 >20 0.043 ± 0.005 0.242 ± 0.014 >20 >20^(a)Compound 8j has a lipid chain at “C” ring position.

TABLE 4 In Vitro Growth Inhibitory Effects of Compounds 8f, 8k-8q, 8t-v,8x-z, and 10 with different “A” Rings against the Proliferation ofMelanoma (A375, B16-F1) and Prostate Cancer Cells (DU145, PC-3, LNCaP,PPC-1) IC₅₀ ± SEM (nM) Compound 8 A Ring B16-F1 A375 DU 145 PC-3 LNCapPPC-1

8f 8k 8l 8m 8n 8o 8p 8q 8t 8u 8v 8x 8y Ph 4-Methyl—Ph 2-Fluoro—Ph3-Fluoro—Ph 4-Fluoro—Ph 3,4-diMeO—Ph 4-Nitro—Ph 4-Cyano—Ph4-Trifluoromethyl—Ph 4-Bromo—Ph 4-Ethyl—Ph 4-Pyridine 2-Pyrimidine 55 ±5  21 ± 10  27 ± 11 287 ± 36  43 ± 21 161 ± 29  56 ± 12  53 ± 16  92 ±16 32 ± 5 70 ± 8 >100000 2300 ± 860 28 ± 5 11 ± 5 30 ± 9 304 ± 25  33 ±14  34 ± 10 38 ± 9  59 ± 24 23 ± 5 13 ± 2 17 ± 2 >100000 4100 ± 740 71 ±4  7 ± 1 114 ± 3  35 ± 3 12 ± 1 102 ± 2  95 ± 5 52 ± 2 50 ± 5 21 ± 4 31± 4 >20000 2813 ± 92  21 ± 1  5 ± 1 82 ± 9 24 ± 2 13 ± 1 69 ± 3 56 ± 130 ± 7 58 ± 4 18 ± 3 27 ± 4 >20000 2657 ± 40  28 ± 4  6 ± 1 53 ± 4 11 ±2  6 ± 1 38 ± 6 39 ± 4 15 ± 4 94 ± 1 44 ± 3 60 ± 5 >20000 2370 ± 85  43± 5  6 ± 1 52 ± 3 21 ± 1  8 ± 1 56 ± 2 34 ± 1 19 ± 2 76 ± 1 21 ± 5 22 ±3 >20000 1186 ± 22  8z 2-Thienyl  38 ± 15 20 ± 7 22 ± 1 17 ± 2  9 ± 1 13± 1 10 H^(a) >100000 >100000 >20000 >20000 >20000 >20000 ^(a)Compound 10has a proton at “A” ring position.

Example 5: Synthesis and In Vitro Cytotoxicity of Additional MethanoneCompounds

The A ring indole of compounds 31 and 32 was synthesized using the sameapproach as 8f described in Scheme 3 above from 1H-indole-5-carbonitrileor 1H-indole-2-carbonitrile as starting material. Crude product waspurified by column chromatography. Description of synthesis of compounds31 and 32 is provided below in Example 11.

(2-(1H-Indol-5-yl)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(Compound 31)

Yield: 36.3%. ¹H NMR (300 MHz, CDCl₃) δ 8.36 (br, 1H), 8.31 (br, 1H),8.21 (s, 1H), 7.92-7.89 (dd, 1H), 7.83 (s, 2H), 7.47 (d, 1H), 7.29 (t,1H), 6.64 (t, br, 1H), 3.98 (s, 3H), 3.97 (m, 6H). MS (ESI) m/z 417.1[M+Na]⁺, 392.9 [M−H]⁻.

(2-(1H-Indol-2-yl)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(Compound 32)

Yield: 45.8%. ¹H NMR (500 MHz, CDCl₃) δ 9.26 (br, 1H), 8.11 (s, 1H),7.67 (d, 2H), 7.46 (s, 2H), 7.42 (d, 1H), 7.29 (t, 1H), 7.16 (t, 1H),7.10 (s, 1H), 3.97 (s, 3H), 3.93 (m, 6H). MS (ESI) m/z 417.1 [M+Na]⁺,392.9 [M−H]⁻.

The activity of compound 31 was assessed by in vitro cytotoxicity assayas described in Example 4 above. It was determined that compound 31exhibited enhanced activity against the PC-3, A375, and B16 cell lines.

TABLE 5 In Vitro Growth Inhibitory Effects of Compounds 31-32 AgainstProliferation of Prostate and Melanoma Cancer Cells IC₅₀ (nM) CompoundStructure RH7777 DU 145 PC-3 LNCaP PPC-1 A375 B16 31

ND ND 7.6 ND ND 25.0 8.3 32

ND ND ND ND ND ND ND ND = not determined.

Example 6: Determining Mechanism of Action for Compound 8f

To understand the target for these highly potent compounds, cell cycleanalysis was performed using compound 8f. LNCaP prostate cancer cellswere exquisitely sensitive to compound 8f (IC₅₀=29 nM). LNCaP cells weretreated with compound 8f (10 to 500 nM) for 24 h prior to staining withpropidium iodide and performing cell cycle analysis. Although compound8f had no effect on cell cycle distribution at a 10 nM (below the IC₅₀),the proportion of cells in G2/M phase increased in proportion to theconcentration of compound 8f at higher concentrations. About 10% ofuntreated cells were observed in G2/M phase, whereas the cells treatedwith more than 50 nM showed a greater proportion of cells in G2/M phase(57, 63, and 49%, respectively, for 50, 200, and 500 nM). The resultsare shown in FIGS. 3A-B. The increase in G2/M phase cells wasaccompanied by a decrease in GI populations, relative to control. Thesedata indicate that compound 8f may inhibit tubulin action in a mannersimilar to paclitaxel, the vinca alkaloids, and cochicine (Margolis etal., “Addition of Colchicine—Tubulin Complex to Microtubule Ends: TheMechanism of Substoichiometric Colchicine Poisoning,” Proc. Nat'l Acad.Sci. USA 74:3466-70 (1977), which is hereby incorporated by reference inits entirety).

Based on these results, an in vitro microtubule polymerization assay wasperformed. Bovine brain tubulin (0.4 mg) (Cytoskeleton, Denver, Colo.)was mixed with various concentrations (0.625-20 μM) of compound 8f andincubated in 120 μl of general tubulin buffer (80 mM PIPES, 2.0 mMMgCl₂, 0.5 mM EGTA, pH 6.9 and 1 mM GTP). The absorbance of wavelengthat 340 nm was monitored every 60 s for 20 min by the SYNERGY 4Microplate Reader (Bio-Tek Instruments, Winooski, Vt.). Thespectrophotometer was set at 37° C. for tubulin polymerization. The IC₅₀value was defined as the concentration which can inhibit 50% ofmicrotubule polymerization. The results are shown in FIG. 4. Comparedwith non-treated control, compound 8f inhibits tubulin polymerization.The effect of 8f on tubulin assembly was examined at concentrations from0.625 μM to 20 μM. The observed results demonstrate that compound 8finhibited tubulin polymerization in a dose-dependent manner with an IC₅₀value of 4.23 μM.

Example 7: In Vitro Cytotoxicity of Compounds 8f and 8n Against A375Melanoma Cell Line

Human A375 malignant melanoma cells were plated at a colony-formingdensity (200 cells per well on six well plates). Cells were grown inDMEM medium (GIBCO, Invitrogen Corp., Carlsbad, Calif.) supplementedwith charcoal-stripped fetal bovine serum (HyClone, Logan, Utah) and anantibiotic-antimycotic solution (Sigma, St. Louis, Mo.) at 37′C in anatmosphere of 95% air and 5% CO₂. Cells were treated with compounds 8fand 8n at different concentrations (0, 0.03, 0.3, and 3 μM). Cells weregrown for 10 days and colonies were fixed with 4% paraformaldehyde inPBS at 4° C. The fixed colonies were washed with distilled water,stained with 0.1% crystalline blue for 30 min and rinsed with distilledwater to remove excess of the dye. Plates were photographed and colonyformations were examined by eye and under the microscope. Both ofcompounds 8f and 8n significantly inhibit melanoma colony formation at0.03 μM. At the two higher concentrations tested (0.3 and 3 μM), colonyformations were completely inhibited, with no colonies visible under themicroscope (FIGS. 5A-B).

Example 8: In Vivo Cytotoxicity of Compound 8n Against MelanomaXenograft Tumor

The efficacy of compound 8n was assessed using B16-F1 mouse melanomacells injected in C57 black mice. B16 tumors will grow in a fullyimmunocompetent host, in which case the tumor progression may moreaccurately replicate melanoma growth. Logarithmic growth phase B16-F1(3.8×10⁵) cells were injected s.c. into the right dorsal flank ofC57BL/6 mice. When tumors were palpable, mice were randomized into acontrol and a treatment group (n=9). Mice were dosed by daily i.p.injection with 30 μl of vehicle (control group) or 8n solution(treatment group, 6 mg/kg). Tumor volume was measured once daily with aTraceable® electronic digital caliper and calculated by using theformula a×b²×0.5, where a and b represented the larger and smallerdiameters, respectively. Body weights were also recorded. Tumor volumewas expressed as cubic millimeters. Data were expressed as Mean±SE foreach group and plotted as a function of time. At the end of treatment,all mice were euthanized by CO₂ inhalation followed by cervicaldislocation. Compound 8n showed significant tumor growth inhibition atthis relatively low dose (6 mg/kg) as shown in FIG. 6. There was nosignificant body weight loss (<5%), and all mice had normal activitiesduring the experiments.

Example 9: Synthesis of Compound 8f Derivatives with Hydrazine or Oxime

Carbonyl group linkers were modified into oxime and hydrazine linkers(compounds 33-36) as illustrated in Scheme 4. Compound 8f was used asstarting material.

To a suspension of 50 mg 8f in 2 mL ethyl alcohol was added a 0.5 mLaqueous solution of 34 mg hydroxylamine hydrochloride. Then 13 mg sodiumhydroxide in 0.5 mL H₂O was added and stirred at room temperature for 10min. Then heating to 60° C. and stirred for 3 h. Oxime isomers 33 and 34were separated from the reaction mixtures by flash chromatograph aswhite crystals with a 50% overall yield.

(Z)-(2-Phenylthiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone oxime(Compound 33)

M.p 150-153° C. ¹H NMR (300 MHz, CDCl₃) δ 11.94 (br, 1H), 8.35 (br, 1H),7.91-7.89 (m, 2H), 7.81-7.75 (d, 1H), 7.50-7.49 (m, 3H), 6.85 (s, 2H),3.73 (s, 6H), 3.71 (s, 3H). MS (ESI) m/z 393.3 [M+Na]⁺, 368.9 [M−H]⁻.

(E)-(2-Phenylthiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone oxime(Compound 34)

M.p 176-177° C. ¹H NMR (500 MHz, DMSO-d₆) δ 11.48 (br, 1H), 7.92-7.90(m, 2H), 7.64 (br, 1H), 7.52-7.48 (d, 1H), 7.52-7.48 (m, 3H), 6.75 (s,2H), 3.75 (s, 6H), 3.72 (s, 3H). MS (ESI) m/z 393.1 [M+Na]⁺, 368.9[M−H]⁻.

To a solution of 2 mL hydrazine in 6 mL ethyl alcohol was added asolution of 230 mg 8f in 2 mL methylene chloride. The mixtures wasrefluxed overnight and absorbed on silicon gel. Hydrazone isomers 35 and36 was separated from the flash chromatograph as white crystals with a56.9% overall yield.

(Z)-4-(Hydrazono(3,4,5-trimethoxyphenyl)methyl)-2-phenylthiazole(Compound 35)

M.p 117-119° C. ¹H NMR (300 MHz, CDCl₃) δ 8.01-7.98 (m, 2H), 7.49-7.46(m, 5H), 7.33 (s, 1H), 6.82 (s, 2H), 3.87 (s, 3H), 3.85 (s, 6H). MS(ESI) m/z 370.1 [M+H]⁺.

(E)-4-(Hydrazono(3,4,5-trimethoxyphenyl)methyl)-2-phenylthiazole(Compound 36)

M.p 65-66° C. ¹H NMR (300 MHz, CDCl₃) δ 8.04-8.00 (m, 2H), 7.44-7.40 (m,3H), 6.95 (s, 1H), 6.62 (s, 2H), 5.62 (s, 2H), 3.93 (s, 3H), 3.87 (s,6H). MS (ESI) m/z 370.1 [M+H]⁺.

TABLE 6 Antiproliferative effects of compounds 33-36 IC₅₀ (μM) CompoundB16 A375 Fibroblast DU145 PC-3 LNCaP PPC-1 33

0.32 0.18 0.36 0.10 0.12 0.19 0.16 34

11.4 7.8 10.1 >1 >1 >1 >1 35

2.0 0.9 1.9 1.21 1.12 1.80 0.87 36

1.8 0.6 1.0 1.21 1.04 1.30 0.97

Example 10: Design of Additional Derivatives

Compound 8f will be further modified to thioketone analogs 41 and 42(Scheme 5 below). Compounds 8a-z will be similarly modified. Thecarbonyl group can be converted into a thiocarbonyl group by the actionof Lawesson's reagent (Jesberger et al., Synthesis 1929-1958 (2003),which is hereby incorporated by reference in its entirety). Thethioketone structure with conjugated aromatic rings is stable relativeto unhindered thioketones. The thiazole compound can be obtained afterdehydrogenation. (Riedrich et al., Angewandte Chemie, InternationalEdition, 46(15):2701-2703 (2007), which is hereby incorporated byreference in its entirety). This conversion will decrease the hydrogenbond acceptor ability from O . . . H in ketone to S . . . H in thione.It will be helpful to examine the importance of hydrogen acceptorposition in these molecules.

New analogs in which the carbonyl has been reduced to an alcohol (43 and44, Scheme 6A below) or reduced to methylene (45 and 46, Scheme 6Bbelow) will be synthesized. The alcohol 43 and 44 can be obtained usingGrignard reaction of intermediate aldehyde with according Grignardreagents. Analogs 45 and 46 can be prepared with Clemmensen reduction ofketone function group to produce the corresponding hydrocarbon. Whencarbonyl is reduced to an alcohol or methylene, the strong hydrogenacceptor C═O reverses to strong hydrogen donor O—H or hydrocarbon, whichtotally loses hydrogen bond effects. This modification will provideinsight as to the importance of carbonyl group and if it has a specificfunction in the anti-cancer activity.

To examine the importance of ketone on antiproliferation in cancercells, this linker will be converted into amide and ester analogs(47-50, Scheme 7 below). Finding activity in any of these series ofanalogs, the different linkages between the rings optimized to enhanceactivity and metabolic stability. As Scheme 7 below shows, consistentwith the results demonstrated in the preceding examples, thiazoline andthiazole rings will be obtained from reaction of benzonitrile (includingsubstituted benzonitrile) and cysteine (Bergeron et al., J. Med. Chem.48:821-831 (2005), which is hereby incorporated by reference in itsentirety). The resulting acid intermediates will be used to prepare theester and amide linkages. These analogs will be compared forantiproliferation activity on prostate cancer cells and/or melanomacells, and control cells, and compared to Compounds 8f and 8n.

Compounds will also be prepared with the trimethoxylphenyl groupreplaced with different substituted aromatic rings, saturated orunsaturated alkyls and various heterocyclic groups as defined herein.This can be accomplished by using different Grignard reagents. Theseanalogs will allow for optimization of the “C” ring with bestactivities, lowest toxicity, and best metabolic stability for prostatecancer, melanoma, and other cancers.

Replacement of the central thiazoline and thiazole rings withcorresponding imidazoline (51), imidazole (52), oxazoline (53) andoxazole (54) ring systems will also be performed. Ethyl benzimidatehydrochloride salt reacted with 2,3-diaminopropanoic acid to giveimidazoline ring system (see Scheme 8A below). (Hsu et al., J. Med.Chem. 23(11), 1232-1235 (1980), which is hereby incorporated byreference in its entirety). Dehydrogenation of imidazolines will afforddesired imidazole compounds. Oxazolines can be prepared according to theclassical condensation of phenyl imino ether with serine ester usingtriethylamine as a base (see Scheme 8B below) (Meyer et al.,Tetrahedron: Asymmetry 14:2229-2238 (2003), which is hereby incorporatedby reference in its entirety). Dehydrogenation of oxazolines will givethe desired oxazole compounds.

Synthesis of (2-(4-bromophenyl)-1H-imidazol-4-yl)(3,4,5trimethoxyphenyl)methanone (121a in the Following Scheme)

Synthesis of 9l:

To a solution of appropriate benzaldehyde (e.g., 4-bromobenzaldehyde)(8l, 100 mmol) in ethanol (400 mL) at 0° C. was added a solution of 40%oxalaldehyde (glyoxal) in water (1.1 equiv) and a solution of 29%ammonium hydroxide in water (10 equiv). After stirring for 2-3 days atRT, the reaction mixture was concentrated and the residue was subjectedto flash column chromatography with dichloromethane as eluent to yieldcompound 91 as a yellow powder. Yield: 10%-30%.

Synthesis of 10la:

To a solution of imidazoles (9l) (2-(4-bromophenyl)-1H-imidazole) (10mmol) in anhydrous THF (200 mL) at 0° C. was added sodium hydride (60%dispersion in mineral oil, 1.2 equiv) and stirred for 20 min.Benzenesulfonyl chloride (1.2 equiv) was added and the reaction mixturewas stirred overnight. After dilution by 200 mL of saturated NaHCO₃solution (aqueous), the reaction mixture was extracted by ethyl acetate(600 mL). The organic layer was dried over magnesium sulfate andconcentrated. The residue was purified by flash column chromatography(hexane: ethyl acetate 2:1) to give a pale solid of compound 10la (e.g.,2-(4-bromophenyl)-1-(phenylsulfonyl)-1H-imidazole). Yield: 40%-95%.

Synthesis of 11la:

To a solution of 2-(4-bromophenyl)-1-(phenylsulfonyl)-1H-imidazole(10la) (5.0 mmol) in anhydrous THF (30 mL) at −78° C. was added 1.7 Mtert-butyllithium in pentane (1.2 equiv) and stirred for 10 min.3,4,5-Trimethoxybenzoyl chloride (1.2 equiv) was added at −78° C. andstirred overnight. The reaction mixture was diluted with 100 mL ofsaturated NaHCO₃ solution (aqueous) and extracted by ethyl acetate (300mL). The organic layer was dried over magnesium sulfate andconcentrated. The residue was purified by flash column chromatography(hexane: ethyl acetate 3:1) to give a white solid of compound 11la(e.g.,(2-(4-bromophenyl)-1-(phenylsulfonyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone).Yield: 5%-45%.

Synthesis of 12la:

To a solution of(2-(4-bromophenyl)-1-(phenylsulfonyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(11la), (2.0 mmol) in THF (25.0 mL) was added 1.0 M tetrabutyl ammoniumfluoride (2 equiv) and stirred overnight. The reaction mixture wasdiluted by 60 mL of saturated NaHCO₃ solution (aqueous) and extracted byethyl acetate (150 mL). The organic layer was dried over magnesiumsulfate and concentrated. The residue was purified by flash columnchromatography (hexane: ethyl acetate 4:1) or recrystallized from waterand methanol to give a white solid of compound 12la((2-(4-bromophenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone).Yield: 80-98%. mp 190-192° C. ¹H NMR (500 MHz, CDCl₃) δ 7.99 (d, J=8.5Hz, 2H), 7.92 (s, 1H), 7.70 (d, J=8.5 Hz, 2H), 7.32 (s, 2H), 4.03 (s,3H), 4.00 (s, 6H). MS (ESI) calcd for C₁₉H₁₇BrN₂O₄, 416.0, found 417.0[M+H]⁺. HPLC2: t_(R) 4.24 min, purity 98.8%.

Synthesis of(2-(p-Tolyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (12da inthe Following Scheme)

Synthesis of 9d:

To a solution of 4-methylbenzaldehyde (8d) (100 mmol) in ethanol (350mL) at 0° C. was added a solution of 40% oxalaldehyde in water (12.8 mL,110 mmol) and a solution of 29% ammonium hydroxide in water (1000 mmol,140 mL). After stirring for 2-3 days at RT, the reaction mixture wasconcentrated and the residue was subjected to flash columnchromatography with dichloromethane as eluent to yield compound 9d(e.g., 2-(p-tolyl)-1H-imidazole) as a yellow powder. Yield: 20%-40%.

Synthesis of 10d:

To a solution of 2-(p-tolyl)-1H-imidazole (9d) (20 mmol) in anhydrousTHF (200 mL) at 0° C. was added sodium hydride (60% dispersion inmineral oil, 1.2 g, 30 mmol) and stirred for 30 min. Benzenesulfonylchloride (2.82 mL, 22 mmol) was added and the reaction mixture wasstirred overnight. After dilution by 100 mL of saturated NaHCO₃ solution(aqueous), the reaction mixture was extracted by ethyl acetate (500 mL).The organic layer was dried over magnesium sulfate and concentrated. Theresidue was purified by flash column chromatography (hexane: ethylacetate 2:1) to give a pale solid 10d (e.g.,1-(phenylsulfonyl)-2-(p-tolyl)-1H-imidazole). Yield: 50%-70%.

Synthesis of 11da:

To a solution of 1-(phenylsulfonyl)-2-(p-tolyl)-1H-imidazole (6.0 mmol)(10d) in anhydrous THF (30 mL) at −78° C. was added 1.7Mtert-butyllithium in pentane (5.3 mL, 9.0 mmol) and stirred for 10 min.Appropriate substituted benzoyl chloride (7.2 mmol) was added at −78° C.and stirred for overnight. The reaction mixture was diluted with 100 mLof saturated NaHCO₃ solution (aqueous) and extracted by ethyl acetate(200 mL). The organic layer was dried over magnesium sulfate andconcentrated. The residue was purified by flash column chromatography(hexane: ethyl acetate 4:1) to give a white solid of 11da (e.g.,(1-(phenylsulfonyl)-2-(p-tolyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone).Yield: 15%-40%.

Synthesis of 12da:

To a solution of(1-(phenylsulfonyl)-2-(p-tolyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(11da, 492 mg, 1.0 mmol) in THF (15.0 mL) was added 1.0 M tetrabutylammonium fluoride (2.0 mL, 2.0 mmol) and stirred overnight. The reactionmixture was diluted by 30 mL of saturated NaHCO₃ solution (aqueous) andextracted by ethyl acetate (80 mL). The organic layer was dried overmagnesium sulfate and concentrated. The residue was recrystallized fromwater and methanol to give a white solid of 12da(2-(p-tolyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone). Yield:88.5%. mp 201-203° C. ¹H NMR (500 MHz, CDCl₃) δ 10.40 (br, 1H), 7.88 (d,J=8.0 Hz, 2H), 7.82 (s, 1H), 7.31 (d, J=8.0 Hz, 2H), 7.24 (s, 2H), 3.96(s, 3H), 3.94 (s, 6H), 2.43 (s, 3H). MS (ESI): calculated forC₂₀H₂₀N₂O₄, 352.10, found 375.2 [M+Na]⁺. HPLC2: t_(R) 15.45 min, purity97.4%.

Optically pure isomers of compounds 8a-8z (from Table 3 above) will alsobe prepared to investigate the importance of chirality at 4-position ofthiazoline. This will be carried out using D- or L-cysteine tosynthesize the chiral intermediate ketones from protected D- orL-cysteine. Condensation of the intermediate ketones with benzonitrilewill afford R- or S-thiazoline isomers. Thiazoles can be prepared bydehydrogenation.

From previous studies on structure-relationship of thiazolidinecarboxylic acid amides, reversed electronic effects of substituents onphenyl in C-2 position of thiazolidine ring resulted in significantdifferent activity on prostate cancer cell lines. Derivatives withdifferent aromatic ring substitutions from various substitutedbenzonitrile reactants will also be prepared (e.g.,4-dimethylamino-benzonitrile, 3-hydroxybenzonitrile,4-methoxybenzonitrile, 3,4-dimethoxybenzonitrile,3,4,5-trimethoxybenzonitrile, 4-acetamidobenzonitrile,4-fluorobenzonitrile, 4-bromobenzonitrile, 4-nitrobenzonitrile,4-cyanobenzonitrile, 3,5-difluorobenzonitrile, 4-methylbenzonitrile,3-bromo-4-fluorobenzonitrile, 2,6-dichlorobenzonitrile,phenylbenzonitrile, indolenitrile and substituted indolylnitriles,pyridine-nitrile and substituted pyridinylnitriles, furan-nitrile andsubstituted furanylnitriles) to induce both electron withdrawing andelectron donating substituents in ring substituent of C-2 position inthiazoline ring. It is believed that the best substituents of C-2phenyl, indolyl, furanyl, thiophen-yl, and pyridinyl groups can be foundafter screening the resulting analogs.

Example 11: Indolyl a Ring Compounds Synthesis of(2-(1H-indol-2-yl)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (32)[FIG. 7]

1H-Indole-2-carbonitrile (60a)

To a cooled solution of indole-2-carboxylic acid (2.0 g, 12.4 mmol) in60 mL of anhydrous Et₂O was added 1.9 mL of SOCl₂ (26 mmol). Afterstirring for 40 min at RT, the ether was removed under reduced pressureat a temperature not exceeding 35° C. The obtained acyl chloride wasdissolved in 40 mL of anhydrous Et₂O and the resulting solution wasadded immediately to a stirred solution of liquid ammonia in 80 ml ofEt₂O. The reaction mixture was stirred at RT for 24 h. The solvent wasthen evaporated under reduced pressure, and the whiteindole-2-carboxamide was crystallized from 50% aq EtOH and dried in air,after which it was dissolved in POCl₃ and heated under reflux for 5 min.The cooled solution was poured onto crushed ice and aq NH₄OH was addedto maintain a basic pH. The aqueous mixture was extracted with Et₂O, andthe extracts were dried over Na₂SO₄ and evaporated. The brownindole-2-carbonitrile 60a (63.3% overall yield from indole-2-carboxylicacid) was obtained. ¹H NMR (500 MHz, CDCl₃) δ 8.56 (br, s, 1H), 7.68 (d,1H, J=8.0 Hz), 7.43-7.34 (m, 2H), 7.24-7.21 (m, 2H). MS (ESI) m/z 144.0(M+H)⁺, 140.8 (M−H)⁻.

(R)-2-(1H-indol-2-yl)-N-methoxy-N-methyl-4,5-dihydrothiazole-4-carboxamide(61a) was synthesized using a method similar to that of 6a-6p (Scheme3). 67.1% yield. ¹H NMR (300 MHz, CDCl₃) δ 9.06 (s, br, 1H), 7.64 (d,2H, J=8.1 Hz), 7.36-7.24 (m, 2H), 7.12 (dt, 1H, J=8.1 Hz, 1.2 Hz), 6.95(d, 1H, J=1.8 Hz), 5.60 (t, br, 1H, J=8.7 Hz), 3.86 (s, 3H), 3.78 (t,1H, J=10.2 Hz), 3.58 (dd, 1H, J=9.0 Hz, 10.2 Hz), 3.30 (s, 3H). MS (ESI)m/z 312.1 (M+Na)⁺, 287.9 (M−H)⁻.

(2-(H-indol-2-yl)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (32) wassynthesized from 61a using the same method as used for 8a-8z, Scheme 3,Method 1. 45.8% yield. ¹H NMR (500 MHz, DMSO-d₆) δ 9.26 (s, 1H), 8.11(s, 1H), 7.66 (d, 1H, J=8.0 Hz), 7.46 (s, 2H), 7.42 (d, 1H, J=8.0 Hz),7.29 (t, 1H, J=7.5 Hz), 7.16 (t, 1H, J=7.5 Hz), 7.10 (s, 1H), 3.97 (s,3H), 3.93 (s, 6H). MS (ESI) m/z 417.1 (M+Na)⁺, 392.9 (M−H)⁻.

Synthesis of(2-(1H-indol-5-yl)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (31)[FIG. 7]

(R)-2-(1-(Phenylsulfonyl)-1H-indol-5-yl)-4,5-dihydrothiazole-4-carboxylicacid (64a)

(R)-2-(1H-Indol-5-yl)-4,5-dihydrothiazole-4-carboxylic acid 63a wassynthesized from 1H-indole-5-carbonitrile using the same method as usedfor 42a of U.S. application Ser. No. 12/981,233 (now US2011/0257196) andU.S. application Ser. No. 1/216,927 (now US2012/0071524), incorporatedherein by reference in their entirety. Briefly, benzonitrile (40 mmol)was combined with L-cysteine (45 mmol) in 100 mL of 1:1 MeOH/pH 6.4phosphate buffer solution. The reaction was stirred at 40° C. for 3days. The precipitate was removed by filtration, and MeOH was removedusing rotary evaporation. To the remaining solution was added 1 M HCl toadjust to pH=2 under 0° C. The resulting precipitate was filtered toyield a white solid 2-phenyl-4,5-dihydrothiazole-4-carboxylic acid 42a,which was used directly to next step without purification. To avigorously stirring solution of 63a (1 mmol) and tetrabutylammoniumhydrogen sulfate (0.15 mmol) in toluene (10 mL) at 0° C. was added 50%aqueous sodium hydroxide (10 mL) and sulfonyl chloride (2 mmol). Theresultant solution was stirred at RT for 6 h. Then 1 N HCl was added toacidify the mixture to pH=2 and extracted with CH₂Cl₂, the organic layerwas separated and dried (MgSO₄); then evaporated to dryness to yield64a, which were used in subsequent steps without further purification.

(R)—N-Methoxy-N-methyl-2-(1-(phenylsulfonyl)-1H-indol-5-yl)-4,5-dihydrothiazole-4-carboxamide(65a) was prepared from 64a a method similar to that of 6a-6p (Scheme3). 57.1% yield. ¹H NMR (500 MHz, CDCl₃) δ 7.92 (m, 2H), 7.77 (m, 3H),7.51 (d, 1H, J=3.0 Hz), 7.46 (t, 1H), 7.35 (t, 1H), 6.61 (d, 1H), 5.58(br, t, 1H) 3.82 (s, 3H), 3.73 (t, 1H), 3.43 (m, 1H), 3.21 (s, 3H). MS(ESI) m/z 452.1 (M+Na)⁺.

(2-(1H-Indol-5-yl)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (31)

To a solution of n-BuLi (1.6 M, 1.7 mL) in 8 mL THF was added a solutionof 3,4,5-trimethoxybromobenzene (2.47 mmol) in 3 mL THF under −78° C.The mixture was allowed to stir for 2 h and a solution of Weinreb amide65a (1.24 mmol) in 3 mL THF was charged. The temperature was allowed toincrease at RT and stirred overnight. The reaction mixture was quenchedwith satd. NH₄Cl, extracted with ethyl ether, dried with MgSO₄. Thesolvent was removed under reduced pressure to yield a crude product,which was refluxed in 1 N NaOH in 5 mL ethanol solution to obtain thedeprotected compound 31 and purified by column chromatography to obtainpure compound as a light yellow solid (36.3%). ¹H NMR (300 MHz, CDCl₃) δ8.36 (br, s, 1H), 8.31 (s, 1H), 8.21 (s, 1H), 7.92, 7.89 (dd, 1H, J=1.8,2.7 Hz), 7.46 (d, 1H,) 7.62 (s, 2H, J=8.7 Hz), 7.29 (t, 1H, J=2.7 Hz),6.64 (br, 1H), 3.97 (s, 6H), 3.97 (s, 3H); MS (ESI) m/z 417.1 (M+Na)⁺,392.9 (M−H)⁻.

Synthesis of (2-Phenyl-thiazol-4-yl)-(3,4,5-trimethoxy-phenyl)-methanone(1-h)

(2-Phenyl-thiazol-4-yl)-(3,4,5-trimethoxy-phenyl)-methanone (1-h)

A mixture of 2-phenyl-4,5-dihydrothiazole-4-carboxylic acid (5 mmol),EDCI (6 mmol) and HOBt (5 mmol) in CH₂Cl₂ (50 mL) was stirred for 10min. To this solution, NMM (5 mmol) and HNCH₃OCH₃ (5 mmol) were addedand stirring continued at RT for 6-8 h. The reaction mixture was dilutedwith CH₂Cl₂ (100 mL) and sequentially washed with water, satd. NaHCO₃,brine and dried over MgSO₄. The solvent was removed under reducedpressure to yield a crude product, which was purified by columnchromatography to get 2-phenyl-4,5-dihydrothiazole-4-carboxylic acidmethoxymethylamide. A solution of2-phenyl-4,5-dihydrothiazole-4-carboxylic acid methoxymethylamide (1equiv) in CH₂Cl₂ was cooled to 0° C., and distilled DBU (2 equiv) wasadded. Bromotrichloromethane (1.7 equiv) was then introduced dropwisevia syringe over 10 min. The reaction mixtures were allowed to warm toRT and stirred overnight. Upon washing with satd. aqueous NH₄Cl (2×50mL), the aqueous phase was extracted with EtOAc (3×50 mL). The combinedorganic layers were dried on MgSO₄, filtered and concentrated in vacuo.The residue was purified by flash chromatography as needed providing2-phenyl-thiazole-4-carboxylic acid methoxymethylamide (73.6%). ¹H NMR(300 MHz, CDCl₃) δ 8.01 (s, 1H), 7.99-7.96 (m, 2H), 7.47-7.44 (m, 3H),3.88 (s, 3H), 3.49 (s, 3H). MS (ESI) m/z 271.0 (M+Na)⁺. To a solution of3,4,5-trimethoxyphenylmagnesium bromide (0.5 N, 3 mL) in 2 mL THF wascharged a solution of 2-phenyl-thiazole-4-carboxylic acidmethoxymethylamide (1 mmol) in 3 mL THF at 0° C. The mixtures werestirred for 30 min until amides disappeared on TLC plates. The reactionmixture was quenched with satd. NH₄Cl, extracted with ethyl ether, driedwith MgSO₄. The solvent was removed under reduced pressure to yield acrude product, which was purified by column chromatography to obtainpure compound 1-h. Yield: 27.3%. ¹H NMR (300 MHz, CDCl₃) δ 8.29 (s, 1H),8.03 (q, 2H), 7.80 (s, 2H), 7.49-7.47 (m, 3H), 3.96 (s, 6H), 3.97 (s,3H). MS (ESI) m/z 378.1 (M+Na)⁺.

Synthesis of (2-(1H-Indol-2-yl)thiazol-4-yl)(1H-indol-2-yl)methanone(8-8)

(2-(1H-Indol-2-yl)thiazol-4-yl)(1H-indol-2-yl)methanone (8-8) wasprepared using the similar method as used of compound 1-h from2-(1H-indol-2-yl)-4,5-dihydrothiazole-4-carboxylic acid and cysteine. ¹HNMR (500 MHz, CDCl₃) δ 9.39 (s, 1H), 8.54 (s, 1H), 8.46 (s, 1H), 8.06(s, 1H), 8.03 (dd, 1H), 7.66 (d, 1H), 7.51 (d, 1H), 7.41 (d, 1H), 7.33(t, 1H), 7.29 (d, 1H), 7.15 (t, 1H), 7.09 (d, 1H), 6.72 (s, 1H). MS(ESI) m/z 366.1 (M+Na)⁺, 341.9 (M−H)⁻.

Synthesis of (2-(1H-indol-2-yl)thiazol-4-yl)(1H-indol-5-yl)methanone(21-21)

(2-(1H-indol-2-yl)thiazol-4-yl)(1H-indol-5-yl)methanone (21-21) wasprepared using the similar method as used of compound 1-h from2-(1H-indol-2-yl)-4,5-dihydrothiazole-4-carboxylic acid and cysteine. ¹HNMR (500 MHz, CDCl₃) δ 9.60 (s, 1H), 9.26 (s, 1H), 8.31 (s, 1H), 8.03(s, 1H), 7.83 (dd, 1H), 7.69 (d, 1H), 7.53-7.49 (m, 2H), 7.41 (t, 1H),7.33 (t, 1H), 7.21-7.18 (m, 2H), 7.13 (s, 1H). MS (ESI) m/z 366.1(M+Na)⁺, 341.9 (M−H)⁻.

Example 12: Synthesis of Selected Indolyl-Benzoyl-Imidazole Compounds

The synthesis of 15xaa is outlined in FIG. 8. This route was originallydesigned for the synthesis of 12xa, but the nonselectivity of thebenzoylation at the indole-2 and imidazole-4 positions resulted in theformation of 15xaa, which is a closely related but bulkier analog of11xaa. The indole-5-carboxaldehyde was protected by a phenylsulfonylgroup on the indole NH to afford intermediate 8xa. 8xa was reacted withglyoxal and ammonium hydroxide to generate the 2-aryl-imidazole 9xa.Protection of the imidazole NH with phenylsulfonyl gave the intermediate10xaa which was coupled with 3,4,5-trimethoxybenzoyl chloride to produce16xaa. Removal of the protecting group from 16xaa provided 15xaa.

Synthesis of 1-(Phenylsulfonyl)-1H-indole-5-carbaldehyde (8xa)

To a solution of indole-3-carboxaldehyde (100 mmol) in ethanol (500 mL)at room temperature was added potassium hydroxide (110 equiv), themixture was stirred until total solubilization. The ethanol wascompletely removed in vacuum and acetone (250 mL) added followed bybenzenesulfonyl chloride (110 equiv). The precipitate was filtered offand the filtrate was concentrated and recrystallized from methanol togive a white solid. Yield: 32.6% ¹H NMR (500 MHz, CDCl₃) δ 10.17 (s,1H), 8.25-8.39 (m, 2H), 7.97-8.09 (m, 3H), 7.69 (t, J=7.33 Hz, 1H), 7.59(t, J=7.5 Hz, 2H), 7.39-7.54 (m, 2H). MS (ESI) calcd for C₁₅H₁₁NO₃S,285.1, found 286.0 [M+H]⁺.

Synthesis of(5-(4-(3,4,5-Trimethoxybenzoyl)-1H-imidazol-2-yl)-1H-indol-2-yl)(3,4,5-trimethoxyphenyl)methanone(15xaa)

To a solution of(1-(phenylsulfonyl)-2-(1-(phenylsulfonyl)-2-(3,4,5-trimethoxybenzoyl)-1H-indol-5-yl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(16xaa) (1 mmol) in ethanol (20 mL) was added sodium hydroxide (10equiv) and stirred overnight in darkness. The reaction mixture wasdiluted by 50 mL of water and extracted by ethyl acetate (250 mL). Theorganic layer was dried over magnesium sulfate and concentrated. Theresidue was purified by flash column chromatography (hexane: ethylacetate 3:1) or recrystallized from water and methanol to give a whitesolid. Yield: 30-95%.

5-(1H-Imidazol-2-yl)-1-(phenylsulfonyl)-1H-indole (9xa)

Yield: 12.0%. ¹H NMR (500 MHz, DMSO-d₆) δ 8.33 (d, J=2.9 Hz, 2H), 8.13(d, J=7.8 Hz, 2H), 7.98-8.04 (m, 1H), 7.62-7.67 (m, 1H), 7.55 (d, J=7.82Hz, 2H), 7.22-7.34 (m, 4H). MS (ESI) calcd for C₁₇H₁₃N₃O₂S, 323.1, found324.0 [M+H]⁺.

1-(Phenylsulfonyl)-5-(1-(phenylsulfonyl)-1H-imidazol-2-yl)-1H-indole(10xaa)

Yield: 23.6%. ¹H NMR (500 MHz, CDCl₃) δ 8.01 (d, J=8.5 Hz, 1H), 7.95 (d,J=7.5 Hz, 2H), 7.73 (d, J=1.0 Hz, 1H), 7.70 (d, J=4.0 Hz, 1H), 7.63-7.66(m, 2H), 7.52-7.56 (m, 3H), 7.31-7.34 (m, 3H), 7.22 (t, J=8.5 Hz, 2H),7.17 (s, 1H), 6.14 (d, J=3.5 Hz, 1H). MS (ESI) calcd for C₂₃H₁₇N₃O₄S₂,463.1, found 464.0 [M+H]⁺.

(1-(Phenylsulfonyl)-2-(1-(phenylsulfonyl)-2-(3,4,5-trimethoxybenzoyl)-1H-indol-5-yl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(16xaa)

Yield: 15.9%. ¹H NMR (500 MHz, CDCl₃) δ 8.18-8.25 (m, 3H), 8.04 (d,J=8.1 Hz, 2H), 7.70-7.78 (m, 2H), 7.61-7.69 (m, 3H), 7.55 (t, J=7.7 Hz,3H), 7.50 (s, 1H), 7.38 (s, 2H), 7.34 (s, 2H), 6.94 (s, 1H), 3.99-4.06(m, 12H), 3.94-3.99 (m, 6H). MS (ESI) calcd for C₄₃H₃₇N₃O₁₂S₂, 851.2,found 852.1 [M+H]⁺.

(5-(4-(3,4,5-Trimethoxybenzoyl)-1H-imidazol-2-yl)-1H-indol-2-yl)(3,4,5-trimethoxyphenyl)methanone(15xaa)

Yield: 45.9%; mp 239-241° C. ¹H NMR (500 MHz, CDCl₃) δ 10.45 (s, 1H),9.44 (s, 1H), 8.41 (s, 1H), 8.04 (d, J=8.5 Hz, 1H), 7.86 (s, 1H), 7.61(d, J=8.5 Hz, 1H), 7.29 (s, 2H), 7.26 (s, 2H), 3.99 (s, 3H), 3.95-3.97(m, 15H). MS (ESI) calcd for C₃₁H₂₉N₃O₈, 571.2, found 572.2 [M+H]⁺.HPLC2: t_(R) 4.09 min, purity 96.3%.

Example 13: Synthesis of(Indolyl)-1H-indazol-4-yl)(3,4,5-trimethoxyphenyl)methanones (17ya),(17yab) and (17yac) (FIG. 9) Synthesis of(2-(1H-indol-3-yl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(17ya)

Synthesis of 1-(phenylsulfonyl)-1H-indole-3-carboxaldehyde (8ya)

To a solution of indole 3-carboxaldehyde (100 mmol) in ethanol (500 mL)at RT was added potassium hydroxide (1.1 equiv). The mixture was stirreduntil total solubilization. The ethanol was completely removed in vacuumand the residual was dissolved in acetone (250 mL) followed by addingbenzenesulfonyl chloride (1.1 equiv, 110 mmol). The reaction mixture wasstirred for half hour. The precipitate was filtered off and the filtratewas concentrated and recrystallized from methanol to give a white solid.Yield: 33%. ¹H NMR (500 MHz, CDCl₃) δ 10.17 (s, 1H), 8.25-8.39 (m, 2H),7.97-8.09 (m, 3H), 7.69 (t, J=7.33 Hz, 1H), 7.59 (t, J=7.5 Hz, 2H),7.39-7.54 (m, 2H). MS (ESI) calcd for C₁₅H₁₁NO₃S, 285.1, found 286.0[M+H]⁺.

Synthesis of 3-(1H-imidazol-2-yl)-1-(phenylsulfonyl)-1H-indole (9ya)

To a solution of 1-(phenylsulfonyl)-1H-indole-3-carboxaldehyde (8ya)(100 mmol) in ethanol (400 mL) at 0° C. was added a solution of 40%oxalaldehyde (glyoxal) in water (1.1 equiv, 110 mmol) and a solution of29% ammonium hydroxide in water (10 equiv, 1000 mmol). After stirringfor 2-3 days at RT, the reaction mixture was quenched by water andextracted by dichloromethane. The organic layer was removed by vacuumand the residue was subjected to flash column chromatography withhexane/ethyl acetate (4:1-2:1) as eluent to yield the titled compound asa yellow powder. Yield: 12%. ¹H NMR (500 MHz, DMSO-d₆) δ 8.33 (d, J=2.9Hz, 2H), 8.13 (d, J=7.8 Hz, 2H), 7.98-8.04 (m, 1H), 7.62-7.67 (m, 1H),7.55 (d, J=7.82 Hz, 2H), 7.22-7.34 (m, 4H). MS (ESI) calcd forC₁₇H₁₃N₃O₂S, 323.1, found 324.0 [M+H]⁺.

Synthesis of1-(phenylsulfonyl)-3-(1-(phenylsulfonyl)-1H-imidazol-2-yl)-1H-indole(10ya)

To a solution of 3-(1H-imidazol-2-yl)-1-(phenylsulfonyl)-1H-indole (9ya)(20 mmol) in anhydrous THF (300 mL) at 0° C. was added sodium hydride(60% dispersion in mineral oil, 1.2 equiv, 24 mmol) and stirred for 20min. Benzenesulfonyl chloride (1.2 equiv, 24 mmol) was added and thereaction mixture was stirred overnight. After dilution by 200 mL ofsaturated NaHCO₃solution (aqueous), the reaction mixture was extractedby ethyl acetate (600 mL). The organic layer was dried over magnesiumsulfate and concentrated. The residue was purified by flash columnchromatography (hexane: ethyl acetate 5:1) to give a white solid. Yield:40%. ¹H NMR (CDCl₃, 300 MHz) δ 8.02-8.08 (m, 4H), 7.72 (d, J=1.5 Hz,1H), 7.35-7.60 (m, 8H), 7.23 (d, J=1.5 Hz, 1H), 7.10-7.16 (m, 3H). MS(ESI) calcd for C₂₃H₁₇N₃O₄S₂, 463.1, found 486.0 [M+Na]⁺.

Synthesis of(1-(phenylsulfonyl)-2-(1-(phenylsulfonyl)-1H-indol-3-yl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(17yaa)

To a solution of1-(phenylsulfonyl)-3-(1-(phenylsulfonyl)-1H-imidazol-2-yl)-1H-indole(10ya) (5.0 mmol) in anhydrous THF (100 mL) at −78° C. was added 1.7 Mtert-butyllithium in pentane (1.2 equiv, 6.0 mmol) and stirred for 10min. A solution of 3,4,5-trimethoxybenzoyl chloride (1.2 equiv, 6.0mmol) in THF was added at −78° C. and stirred overnight. The reactionmixture was quenched with 100 mL of saturated NaHCO₃ solution (aqueous)and extracted by ethyl acetate (300 mL). The organic layer was driedover magnesium sulfate and concentrated. The residue was purified byflash column chromatography (hexane: ethyl acetate 3:1) to give a whitesolid. Yield: 30%. ¹H NMR (500 MHz, CDCl₃) δ 8.09 (d, J=10 Hz, 1H), 8.04(d, J=10 Hz, 2H), 7.91 (s, 1H), 7.76 (d, J=5 Hz, 2H), 7.65 (t, J=10 Hz,1H), 7.55-7.58 (m, 5H), 7.40 (s, 2H), 7.33-7.36 (m, 3H), 7.25 (t, J=10Hz, 1H), 4.05 (s, 3H), 4.03 (s, 6H). MS (ESI) calcd for C₃₃H₂₇N₃O₈,657.0, found 680.1 [M+Na]⁺.

Synthesis of(2-(1H-indol-3-yl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(17ya)

To a solution of(1-(phenylsulfonyl)-2-(1-(phenylsulfonyl)-1H-indol-3-yl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(17yaa) (1 mmol) in ethanol (40 mL) and water (4 mL) was added sodiumhydroxide (10 equiv, 10 mmol) and stirred overnight under refluxingcondition in darkness. The reaction mixture was diluted by 50 mL ofwater and extracted by ethyl acetate (200 mL). The organic layer wasdried over magnesium sulfate and concentrated. The residue was purifiedby flash column chromatography (hexane: ethyl acetate 1:1) to give ayellow solid. Yield: 60%. ¹H NMR (500 MHz, CD₃OD) δ 8.31 (d, J=6.5 Hz,1H), 7.99 (s, 1H), 7.90 (s, 1H), 7.48-7.52 (m, 3H), 7.24-7.28 (m, 2H),4.00 (s, 6H), 3.93 (s, 3H). MS (ESI) calcd for C₂₁H₁₉N₃O₄, 377.1, found400.1 [M+Na]⁺. Mp 208-210° C.

Synthesis of(2-(1-(Phenylsulfonyl)-1H-indol-3-yl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(17yab)

To a solution of compound 17yaa (66 mg) in THF (1.0 ml) was added 1.0 Mtetrabutyl ammonium fluoride (0.4 mL, 0.4 mmol) and stirred overnight.The reaction mixture was diluted by 20 ml of saturated NaHCO₃ solution(aqueous) and extracted by ethyl acetate (20 mL). The organic layer wasdried over magnesium sulfate and concentrated. The residue was purifiedby flash column chromatography (hexane:ethyl acetate, 2:1) to give apale white solid. Yield: 45%. Mp 110-112° C. ¹H NMR (CDCl₃, 500 MHz) δ8.40-8.42 (m, 2H), 8.09 (d, J=8.0 Hz, 1H), 7.93-7.98 (m, 4H), 7.59 (t,J=7.5 Hz, 1H), 7.41-7.49 (m, 5H), 4.01 (s, 3H), 3.97 (s, 6H). MS (ESI)calcd for C₂₇H₂₃N₃O₆S, 517.1, found 540.0 [M+Na]⁺. HPLC: t_(R) 6.81 min,purity 96.3%.

Synthesis of(1-methyl-2-(1-(methyl)-1H-indol-3-yl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(17yac)

To a solution of 17ya (75 mg, 0.2 mmol) in anhydrous THF (20 ml) at 0°C. was added sodium hydride (60% dispersion in mineral oil, 20 mg, 0.5mmol) and stirred for 20 min. Methyl iodide (70 mg, 0.5 mmol) was added,and the reaction mixture was stirred 1 h. After dilution by 20 ml ofsaturated NaHCO₃ solution (aqueous), the reaction mixture was extractedby ethyl acetate (60 ml). The organic layer was dried over magnesiumsulfate and concentrated. The residue was recrystallized from water andmethanol to give a white solid. 75% yield. Mp 164-166° C. ¹H NMR (CDCl₃,500 MHz) δ 8.30 (d, J=7.5 Hz, 1H), 8.01 (s, 1H), 7.87 (s, 1H), 7.41 (t,J=8.5 Hz, 1H), 7.39 (s, 1H), 7.35 (t, J=7.0 Hz, 1H), 7.23 (t, J=7.0 Hz,1H), 3.98 (s, 6H), 3.95 (s, 3H), 3.91 (s, 3H), 3.89 (s, 3H). MS (ESI)calcd for C₂₃H₂₃N₃O₄, 405.2, found 406.4 [M+H]⁺. HPLC: t_(R) 4.80 min,purity>99%.

Example 14: Synthesis of(Benzofuranyl-1H-Imidazol-4-yl)(3,4,5-Trimethoxyphenyl)Methanone(17ya(i)) and(Benzothiophenyl-1H-Imidazol-4-yl)(3,4,5-Trimethoxyphenyl)Methanones(17ya(ii))

Synthesis of(2-(Benzofuran-3-yl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(17ya(i)), and(2-(benzo[b]thiophen-3-yl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(17ya(ii))

10 min. A solution of 3,4,5-trimethoxybenzoyl chloride (1.38 g, 6.0mmol) in THF was added at −78° C. and stirred overnight. The reactionmixture was quenched with 100 ml of saturated NaHCO₃ solution (aqueous)and extracted by ethyl acetate (300 ml). The organic layer was driedover magnesium sulfate and concentrated. The residue was used for nextstep by adding 10 mL of 1.0 M tetrabutyl ammonium fluoride and stirredovernight. The reaction mixture was diluted by 200 ml of saturatedNaHCO₃ solution (aqueous) and extracted by ethyl acetate (200 ml). Theorganic layer was dried over magnesium sulfate and concentrated. Theresidue was purified by flash column chromatography (hexane: ethylacetate 3:1) to give a white solid. 17ya (i): 4.7% yield. Mp 208-210° C.¹H NMR (CDCl₃, 500 MHz) δ 8.77 (s, 1H), 8.12 (d, J=7.6 Hz, 1H), 7.90 (s,1H), 7.632-7.65 (m, 1H), 7.44-7.49 (m, 2H), 7.29 (s, 2H), 3.99 (s, 3H),3.93 (s, 6H). MS (ESI) calcd for C₂₁H₁₈N₂O₅, 378.1, found 377.1[M−H]⁻.HPLC1: t_(R) 5.18 min, purity 98.8%. 17ya(ii): 3.2% yield. Mp 185-187°C. ¹H NMR (CDCl₃, 500 MHz) δ 10.62 (s, 1H), 8.74 (d, J=5.0 Hz, 1H), 8.06(s, 1H), 7.92-7.95 (m, 2H), 7.48-7.54 (m, 2H), 7.29 (s, 2H), 3.99 (s,3H), 3.97 (s, 6H). MS (ESI) calcd for C₂₁H₁₈N₂O₄S, 394.1, found392.8[M−H]⁻. HPLC: t_(R) 5.38 min, purity 95.6%.

Example 15: Novel Anti-Tubulin Compounds Overcome P-GlycoproteinMediated Multidrug Resistance

The P-glycoprotein (P-gp) system appears to be a primary physiologicalmechanism of multidrug resistance (MDR) which acts as an ATP-dependentdrug efflux pump, actively removing a variety of structurally diversecytotoxic compounds. Enhanced efflux of these compounds reduces theirintracellular accumulation and so reduces their cytotoxicity. Therefore,novel compounds which are not susceptible to drug resistance could be ofhigh therapeutic and economic value. In addition to P-gp, clinicallyused antitubulin agents have other resistance mechanisms such as changesin microtubule dynamics and mutations in β-tubulin which are known tolimit sensitivity to the taxanes. The anti-tubulin compounds of theinvention were tested against an ovarian cancer cell line OVCAR-8(parent) and P-gp over-expressing NCI/ADR-RES cell line (Table 7A).

Results:

TABLE 7A Antiproliferative Activity of Selected Compounds against P-gpover-expressed MDR cell lines. IC₅₀ (nM) Resistance Compound OVCAR-8NCI/ADR-RES factor

33 ± 3  13 ± 0.8 0.4

34 ± 2 14 ± 1 0.4

10 ± 3 4 ± 2 0.4

26 ± 2 11 ± 2 0.4

46 ± 6 27 0.6

28 21 0.8

44 ± 3 25 ± 6 0.6

35 ± 2 13 ± 1 0.4 paclitaxel^(*) 4.7 ± 0.1 6263 ± 634 1333 vinblastine3.9 ± 0.1 582 ± 57 149 colchicine 17 ± 1  1113 ± 79  65

Notably, the anti-tubulin compounds of the invention demonstratedequipotent antiproliferative effects against OVCAR-8 and NCI/ADR-REScell lines, suggesting that they are not P-gp substrates and that theyfunction in a P-gp-independent manner. This feature is distinct fromthat of paclitaxel, vinblastine, and colchicine in NCI/ADR-RES cells.

The phenyl amino thiazole compounds 5-a, 5-Hb, 5-c and 5-d demonstratedpotent activity in a number of prostate cancer cell lines. Unexpectedly,the phenyl amino imidazole compound 5-e demonstrated no activity(IC₅₀>1000 nM in LNCaP, PC-3, DU-145, and PPC-1) in these prostatecancer cell lines. The positive controls for this experiment were 55 and17ya which demonstrated IC₅₀ values between 7.5 nM and 24.1 nM in thesame cell lines (Table 7B).

TABLE 7B IC₅₀ ± SEM (nM) B16-F1 A375 DU 145 PC-3 LNCaP PPC-1

 65 ± 12 45 ± 8 70 ± 4 57 ± 3 51 ± 1 54 ± 1

ND ND 35 ± 1 38 ± 2 35 ± 1 36 ± 1

ND ND 63 ± 1 43 ± 1 41 ± 1 37 ± 1

ND 25 ± 7 73 ± 1 33 ± 1 45 ± 1 36 ± 1

55 ± 5 28 ± 5 71 ± 4 21 ± 1 28 ± 4 43 ± 5

2127 ± 351 1111 ± 108  839 ± 719 786 ± 89 658 ± 117 701 ± 307

ND ND >1000 >1000 >1000 >1000

ND ND 24 ± 6 12 ± 1 13 ± 1 15 ± 1

ND ND 11 ± 1  5 ± 2  8 ± 2  8 ± 1

Example 16: Antiproliferative Activity of Compounds of the Invention

The antiproliferative activity of analogs prepared by the methods of theinvention are shown in Table 8.

TABLE 8 IC₅₀ (nM) Structure ID LNCaP PC-3 DU 145 PPC-1 A375 B16-F1 WM164

8-8 346 704 580 230 318 570 404

9-9 ~10000 ~10000 ~10000 ~10000

10-10 658 786 839 701 1111 2127 661

11-11 >10000 >10000 ~10000 ~10000 3470 4900 4700

12-12 >10000 >10000 >10000 >10000 >10000 >10000

13-13 >10000 >10000 >10000 >10000 >10000 >10000 >10000

14-14 >10000 >10000 >10000 >10000 >10000 >10000

16-16 >10000 >10000 >10000 >10000 15200 6900

17-17 2100 1900 2600 1300 4300 9800

18-18 ~10000 ~10000 ~10000 ~10000

19-19 >20000 >20000 >20000 >20000 >20000 >20000 20-20 1452 >10000 642633 2300 3100 1300

21-21 314 403 435 216 383 924 408

22-22 >20000 >20000 >20000 >20000 >20000 >20000

23-23 ~10000 ~10000 ~10000 ~10000

24-24 >10000 >10000 >10000 >10000 >10000 >10000 >10000

25-25 48 44 24 13 20 38

26-26 23 16 16 15 11 14

29-29 1788 >10000 >10000 >10000 >10000 >10000

30-30 >10000 >10000 >10000 >10000 >10000 >10000

32-32 1664 2291 4601 1170 2700 >10000 2600

33-33 >2000 >2000 >2000 >2000 9800 >20000

34-34 >10000 >10000 >10000 >10000 >10000 >10000

35-35 1500 40100 21900 15000

39-39 4300 32500 16800 21400

40-40 13400 19600 18400 6200

41-41 15750 18170 17040 >20000

42-42 43590 23790 24880 >20000

43-43 12690 14720 17210 >20000

17ya 12 10 17 21 17.35 32.94 12.08

17yab 233.7 148.3 592.1 208.9 481.2 538.7 467.6

15xaa 1068 2628 5917 4575 1800 1390 1700

16xaa >10000 >10000 >10000 >10000 >10000 >10000 >10000

Example 17: In Vitro and In Vivo Pharmacology of Compounds 17ya, 12fa,and 55 Materials and Methods

Cell Culture and Cytotoxicity Assay of Prostate Cancer.

All prostate cancer cell lines (LNCaP, PC-3, and DU145, PPC-1) wereobtained from ATCC (American Type Culture Collection, Manassas, Va.,USA). Human PC-3_TxR, was resistant to paclitaxel and used as a MDRmodel compared with PC-3. Cell culture supplies were purchased fromCellgro Mediatech (Herndon, Va., USA). All cell lines were used to testthe antiproliferative activity of compounds 17ya, 12fa(((2-(4-Chlorophenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone),and 55((2-(1H-indol-5-ylamino)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone)by sulforhodamine B (SRB) assay. All cancer cell lines were maintainedin RPMI 1640 media with 2 mM glutamine and 10% fetal bovine serum (FBS).

In Vitro Microtubule Polymerization Assay.

Porcine brain tubulin (0.4 mg) (Cytoskeleton, Denver, Colo.) was mixedwith 1 and 5 μM of the test compound or vehicle (DMSO) and incubated in100 μL of buffer (80 mM PIPES, 2.0 mM MgCl₂, 0.5 mM EGTA, pH 6.9 and 1mM GTP). The absorbance at 340 nm wavelength was monitored every min for15 min (SYNERGY 4 Microplate Reader, Bio-Tek Instruments, Winooski,Vt.). The spectrophotometer was maintained at 37° C. for tubulinpolymerization.

Metabolic Incubations.

Metabolic stability studies were conducted by incubating 0.5 μM of testcompounds in a total reaction volume of 1 mL containing 1 mg/mLmicrosomal protein in reaction buffer [0.2 M of phosphate buffersolution (pH 7.4), 1.3 mM NADP⁺, 3.3 mM glucose-6-phosphate, and 0.4U/mL glucose-6-phosphate dehydrogenase] at 37° C. in a shaking waterbath. The NADPH regenerating system (solution A and B) was obtained fromBD Biosciences (Bedford, Mass.). For glucuronidation studies, 2 mMUDP-glucuronic acid (Sigma, St. Louis, Mo.) cofactor in deionized waterwas incubated with 8 mM MgCl₂, 25 μg of alamethicin (Sigma, St. Louis,Mo.) in deionized water, and NADPH regenerating solutions (BDBiosciences, Bedford, Mass.) as described previously. The total DMSOconcentration in the reaction solution was approximately 0.5% (v/v).Aliquots (100 μL) from the reaction mixtures used to determine metabolicstability were sampled at 5, 10, 20, 30, 60, and 90 min. Acetonitrile(150 μL) containing 200 nM of the internal standard was added to quenchthe reaction and to precipitate the proteins. Samples were thencentrifuged at 4,000 g for 30 min at RT, and the supernatant wasanalyzed directly by LC-MS/MS.

Analytical Method.

Sample solution (10 μL) was injected into an Agilent series HPLC system(Agilent 1100 Series Agilent 1100 Chemstation, Agilent Technology Co,Ltd). All analytes were separated on a narrow-bore C18 column (AlltechAlltima HP, 2.1×100 mm, 3 μm, Fisher, Fair Lawn, N.J.). Two gradientmodes were used. For metabolic stability studies, gradient mode was usedto achieve the separation of analytes using mixtures of mobile phase A[ACN/H₂O (5%/95%, v/v) containing 0.1% formic acid] and mobile phase B[ACN/H₂O (95%/5%, v/v) containing 0.1% formic acid] at a flow rate of300 μL/min. Mobile phase A was used at 10% from 0 to 1 min followed by alinearly programmed gradient to 100% of mobile phase B within 4 min,100% of mobile phase B was maintained for 0.5 min before a quick ramp to10% mobile phase A. Mobile phase A was continued for another 10 mintowards the end of analysis.

A triple-quadruple mass spectrometer, API Qtrap 4000™ (AppliedBiosystems/MDS SCIEX, Concord, Ontario, Canada), operating with aTurbolonSpray source was used. The spraying needle voltage was set at 5kV for positive mode. Curtain gas was set at 10; Gas 1 and gas 2 wereset 50. Collision-Assisted-Dissociation (CAD) gas at medium and thesource heater probe temperature at 500° C. Multiple reaction monitoring(MRM) mode, scanning m/z 378-210 (17ya), m/z 373-205 (12fa), m/z 410-242(55) and m/z 309-171 (internal standard), was used to obtain the mostsensitive signals. Data acquisition and quantitative processing wereaccomplished using Analyst™ software, Ver. 1.4.1 (Applied Biosystems).

Aqueous Solubility.

The solubility of drugs was determined by Multiscreen Solubility FilterPlate (Millipore Corporate, Billerica, Mass.) coupled with LC-MS/MS.Briefly, 198 μL of phosphate buffered saline (PBS) buffer (pH 7.4) wasloaded into 96-well plate, and 2 μL of 10 mM test compounds (in DMSO)was dispensed and mixed with gentle shaking (200-300 rpm) for 1.5 hoursat RT (N=3). The plate was centrifuged at 800 g for 10 min, and thefiltrate was used to determine its concentration and solubility of testcompound by LC-MS/MS as described previously.

Pharmacokinetic Study.

Male ICR mice (n=3 per group) 6 to 8 weeks of age were purchased fromHarlan Inc., and used to examine the pharmacokinetics (PK) of 17ya,12fa, and 55. All compounds (10 mg/kg) were dissolved in DMSO/PEG300(1/9) and administered by a single intravenously (i.v.) injection (50μL) into the tail vein. Blood samples were collected at 5, 15, and 30min, 1, 1.5, 2, 3, 4, 8, 12, and 24 h after i.v. administration. Micewere given (p.o.) by oral gavage at 20 mg/kg (in Tween80/DMSO/H₂O,2/2/6) of each test compound to evaluate their oral bioavailability.Blood samples were collected at 0.5, 1, 1.5, 2, 3, 4, 8, 12, and 24 hafter p.o. administration.

Female Sprague-Dawley rats (n=3; 254±4 g) were purchased from HarlanInc. (Indianapolis, Ind.). Rat thoracic jugular vein catheters werepurchased from Braintree Scientific Inc. (Braintree, Mass.). On arrivalat the animal facility, the animals were acclimated for 3 days in atemperature-controlled room (20-22° C.) with a 12 h light/dark cyclebefore any treatment. Compounds 17ya, 12fa, and 55 were administeredi.v. into the thoracic jugular vein at a dose of 5 mg/kg (inDMSO/PEG300, 1/9). An equal volume of heparinized saline was injected toreplace the removed blood, and blood samples (250 μL) were collected viathe jugular vein catheter at 10, 20, 30 min, and 1, 2, 4, 8, 12, 24 h.Rats were given (p.o.) by oral gavage at 10 mg/kg (in Tween80/DMSO/H₂O,2/2/6) of each test compound to evaluate their oral bioavailability. Allblood samples (250 μL) after oral administration were collected via thejugular vein catheter at 30, 60, 90 min, 120 min, 150 min, 180 min, 210min, 240 min, and 8, 12, 24 h. Heparinized syringes and vials wereprepared prior to blood collection. Plasma samples were prepared bycentrifuging the blood samples at 8,000 g for 5 min. All plasma sampleswere stored immediately at −80° C. until analyzed.

Analytes were extracted from 100 μL of plasma with 200 μL ofacetonitrile containing 200 nM the internal standard. The samples werethoroughly mixed, centrifuged, and the organic extract was transferredto autosampler for LC-MS/MS analysis.

PC-3_TxR Xenograft Studies.

PC-3_TxR cells (10×10⁷ per mL) were prepared in RPMI1640 growth mediacontaining 10% FBS, and mixed with Matrigel (BD Biosciences, San Jose,Calif.) at 1:1 ratio. Tumors were established by injecting 100 μL of themixture (5×10⁶ cells per animal) subcutaneously (s.c.) into the flank of6-8-week-old male athymic nude mice. Length and width of tumors weremeasured and the tumor volume (mm³) was calculated by the formula,π/6×L×W², where length (L) and width (W) were determined in mm. When thetumor volumes reached 300 mm³, the animals bearing PC-3_TxR tumors weretreated with vehicle [Tween80/DMSO/H₂O (2/2/6)], or 17ya (10 mg/kg)orally. The dosing schedule was 3 times a week for four weeks.

Results

17a and 55 Exhibit Broad Cytotoxicity in Cells, IncludingMultidrug-Resistant Cells.

The ability of 17ya and 55 to inhibit the growth of cancer cell lineswas evaluated using SRB assay (Table 9). Both compounds inhibited thegrowth of several human cancer cell lines, including five prostate andone glioma cancer cell lines, with IC₅₀ values in the low nanomolarrange. 17ya exhibited 1.7-4.3 fold higher potency than 55 in these celllines. Paclitaxel-resistant PC-3 (PC-3/TxR) cell line thatover-expresses P-glycoprotein (P-gp), was used to study the effect ofdrug resistance on 17ya and 55 and to compare against its parent, PC-3cell line. The IC₅₀ values of docetaxel were 1.2±0.1 nM and 17.7±0.7 nMin PC-3 and PC-3/TxR cells, respectively. 17ya and 55 were bothequipotent against parent PC-3 and PC-3/TxR, whereas paclitaxel anddocetaxel exhibited relative resistance of 85- and 15-fold,respectively. These data indicate that both 17ya and 55 circumventP-gp-mediated drug resistance.

TABLE 9 Cytotoxicity data of 17ya and 55 Cytotoxicity [IC₅₀ values, mean± SD nM 17ya 55 Paclitaxel Cell line Type

PC-3 Prostate 5.2 ± 02  16.5 ± 1.5   0.6 ± 0.05 PC-3/ Prostate     2.1 ±0.1 (0.4)     6.7 ± 0.4 (0.4)     51 ± 2.3 (85) T × R LNCaP Prostate 12± 0.1 27 ± 0.6 1.7 ± 0.2 Du-145 Prostate 17 ± 0.2 38 ± 0.6 5.1 ± 0.1PPC-1 Prostate 21 ± 0.1 36 ± 0.4 2.3 ± 0.8 U87MG Glioma 10 ± 0.6 22 ±3.0 NR IC₅₀ values (mean ± SD) were determined after 96 h treatment (N =3). Paclitaxel was used as a positive control. Data in parenthesisindicated resistance factor when compared IC₅₀ values in PC-3 and PC-3/T× R. NR, Not Reported.

17ya and 55 bind to colchicine-binding site on tubulin, inhibit tubulinpolymerization, and induce cell apoptosis (FIG. 10). A competitive massbinding assay was developed to study the interaction of small moleculeinhibitors with tubulin. In this study, varying concentrations of 17yaor 55 were used to compete with colchicine-tubulin binding. Bothcompounds competed effectively with colchicine for tubulin binding (FIG.10A); however, their competitive binding curves deviated substantiallyfrom zero at higher concentrations when compared to podophylltoxin, aknown potent colchicine-site binding ligand. This suggests that both17ya and 55 exhibited less affinity than podophylltoxin or theypartially bind to the colchicine-binding site. Vinblastine, the negativecontrol, did not inhibit the colchicine-tubulin binding, successfullydemonstrating the specificity of this competitive mass binding assay.

Porcine brain tubulin (>97% pure) was incubated with 17ya or 55 (5 μM)to test their effect on tubulin polymerization (FIG. 10B). 17ya and 55inhibited tubulin polymerization by 47% and 40% at 15 min, respectively.Colchicine at 5 μM was used as a positive control and inhibited tubulinpolymerization by 32%. These data suggest that both 17ya and 55 haveslightly greater inhibition of tubulin polymerization than colchicine.Therefore, the molecular mechanism of these compounds is binding to thecolchicine-binding site, inhibiting tubulin polymerization, and inducingcytotoxicity.

PC-3 and PC-3/TxR cells were exposed to 0.8 to 600 nmol/L of 17ya, 55,or docetaxel for 24 h. The levels of DNA-histone complexes were used torepresent cell apoptosis. Both 17ya and 55 were equally potent to inducecell apoptosis in PC-3 (FIG. 10C) and PC-3/TxR (FIG. 10D) in 24 h.Though, docetaxel was highly potent to induce apoptosis of PC-3 cells,it was weaker in PC-3/TxR cells due to over-expression of P-gp.

17ya and 55 Exhibited Favorable Drug-Like Properties.

Drug-like properties, such as metabolic stability, permeability, aqueoussolubility, and drug-drug interactions, were examined for 17ya and 55(Table 10A). 17ya exhibited greater metabolic stability, and aqueoussolubility than 55. Both chemicals exhibited more than adequatepermeability values, suggesting their potential to be orally used. Inaddition, both 17ya and 55 showed high IC₅₀ values in micromolar rangeon CYP enzyme inhibition assays, indicating that both compounds mayavoid drug-drug interactions through main CYP liver enzymes. Overall,both compounds exhibited favorable drug-like properties.

TABLE 10A Drug-like properties of compound 17a and 55. Metabolicstability, permeability, solubility, and potential drug-druginteractions were evaluated. Each value represents the mean fromduplicate studies. positive Measurment Units 17ya 55 controls (mean)Metabolic stability half-life in human liver min >60 28 Verapamilmicrosomes (12) Permeability P_(app(A→B)) in CaCO-2 assay 10⁻⁶ cm/s 3699 Propranolol (19) Aqueous solubility μg/mL >75 19 1 h (1.1) Drug-druginteractions IC₅₀ value in Cyp3A4 μM 20 5.5 Ketoconazole (substrate:Testosterone) (0.02) IC₅₀ value in Cyp2D6 μM >50 34 Quinindine(substrate: Dextromethorphan) (0.1) IC₅₀ value in Cyp2C19 μM 6.6 5.3Ticlopidine (substrate: (S)-mephenytoin) (0.37) IC₅₀ value in Cyp2C9 μM17 4.9 Sulfaphenazole (substrate: Diclofenac) (0.5) IC₅₀ value in Cyp1A2μM 9.2 8.1 Furafylline (substrate: Phenacetin) (2.2)

As shown in Table 10B, 17ya had a half-life of 80 min by phase Ireaction, suggesting that 17ya was stable in phase I metabolicprocesses. The half-life (90 min) in the presence of UDP-glucuronic acidwas similar to that observed in its absence. These data suggested that17ya is stable in human liver microsomes, and it was hoped that lowclearance and long half-life will be obtained in human. On the otherhand, 55 exhibited 30 and 43 min as half lives when it was in thepresence and absence of UDP-glucuronic acid, respectively. Compound 12fashows the half-life with 44 in phase I. These data suggested that allthree compounds showed acceptable stability in human liver microsomes,and 17ya is more stable than 12fa and 55. When investigating theirmetabolism, it was found that 12fa and 55 exhibited higher levels ofketone-reduction (data not shown), suggesting that 12fa and 55 are morelabile than 17ya.

Compound 17ya exhibited great aqueous solubility, compounds 12fa and 55showed acceptable solubility.

Compound 17ya contained an imidazole ring, and this ring improvedaqueous solubility, resulting in >75 μg/mL aqueous solubility (Table 10Aor 10B). Compounds 12fa and 55 exhibited less aqueous solubility, andexhibited 12 and 19 μg/mL, respectively. Overall, 17ya demonstrated agreat aqueous solubility, and 12fa and 55 showed acceptable aqueoussolubility, and much improved over 1-h. The greater solubility of 12fatranslated into much improved oral bioavailability compared to 1-h (35%vs. 3.3% in rat). Similarly for 17ya and 55, aqueous solubilitycorrelated with much improved oral bioavailability as discussed infra(Table 11).

Pharmacokinetic Studies of 17ya and 55 in Mice, Rats and Dogs.

The pharmacokinetic parameters of 17ya and 55 given in a single (i.v. orp.o.) dose in ICR mice, Sprague-Dawley rats, and beagle dogs aresummarized in Table 11. 17ya exhibited low clearance in mice and rats,suggesting that 17ya exhibited metabolic stability, and minimalfirst-pass metabolism in these species. In addition, 17ya had moderatevolume of distribution in mice and rats, indicating that it may properlydistribute into tissues, including tumors. Unlike in mice and rats,surprisingly, the total clearance of 17ya in dogs was high. Two abundantmetabolites in dog plasma, a hydroxylated metabolite and an unknownmetabolite with +34 m/z of the parent (data not shown), were consistentwith those found in dog liver microsomes. In summary, higher clearanceand lower oral exposure was obtained for 17ya compared to 55 in dogs,but not in mice and rats. In addition, 17ya exhibited abundantmetabolites only in dog liver microsomes, but not in mouse, rat or humanliver microsomes (data not shown). 17ya showed acceptable 21%, 36%, and50% oral bioavailability in rats, mice, and dogs, respectively.Meanwhile, 55 had low clearance in rats, and moderate clearance in miceand dogs. Similar to 17ya, 55 exhibited moderate volume of distributionin these species. 55 had constant oral bioavailability rates among threespecies (24%-36%). These properties indicate that both 17ya and 55 arepotential orally available tubulin inhibitors.

TABLE 11 Pharmacokinetic studies of compounds 17ya and 55 in mice, rats,and dogs. 17ya 55 IV PO IV PO Mouse PK (N = 3) Dose, mg/kg 10 20 10 20Clearance, 19 NR 40 NR mL/min/kg Vss, L/kg 2.9 NR 1.3 NR t_(1/2), min101 339 46 126 AUC, 540 384 249 171 min * μg/mL C_(max), ng/mL 4800 15607739 1253 F, % 36% 34% Rat PK (N = 3) Dose, mg/kg 5 10 5 10 Clearance,9.5 ± 2.3 NR  10 ± 1.4 NR mL/min/kg Vss, L/kg 1.8 ± 0.2 NR 1.0 ± 0.1 NRt_(1/2), min 139 ± 24  206 ± 12   73 ± 5.0 350 ± 214 AUC, 553 ± 143 233± 134 509 ± 73  246 ± 163 min * μg/mL C_(max), ng/mL 3672 ± 519  999 ±445 4609 ± 55  757 ± 520 F, % 21% 24% Dog PK (N = 4) Dose, mg/kg 2 5 2 5Clearance, 109 ± 29  NR  15 ± 3.2 NR mL/min/kg Vss, L/kg 94 ± 95 NR 0.9± 0.2 NR t_(1/2), min 2757 ± 1573 1695 ± 439  82 ± 15 191 ± 9.0  AUC,18.5 ± 4.7  23.1 ± 11.3 141 ± 30  128 ± 154 min * μg/mL C_(max), ng/mL400 ± 118 210 ± 133 2552 ± 576   862 ± 1010 F, % 50% 36%

17ya and 55 Inhibit Paclitaxel Resistant Prostate (PC-3/TxR) XenograftsGrowth.

PC-3 (FIG. 11A) and paclitaxel-resistant prostate cancer (PC-3/TxR)(FIG. 11B) cells were inoculated in nude mice and the tumor volumes wereallowed to reach about 150-300 mm³. Docetaxel (10 or 20 mg/kg), which isin clinic for prostate cancer, was used to evaluate its effectiveness inmodels of P-gp-mediated drug resistance in vivo. PC-3/TxR tumor wasfound to be fast-growing and the volume reached 1500-2500 mm³ at thetermination of the study. Though 10 and 20 mg/kg intravenouslyadministered docetaxel exhibited a dose response in both models (FIGS.11A and 11B), the tumor growth inhibition (TGI) effect decreased from84% TGI in PC-3 tumors to 14% TGI in PC-3/TxR tumors when intravenouslydosed at 10 mg/kg (Table 12). In addition, at the higher dose (20mg/kg), docetaxel elicited partial regression (>100% TGI) of PC-3tumors, but barely 56% TGI in PC-3/TxR tumors. The effectiveness ofdocetaxel in PC-3/TxR tumors was dramatically decreased when compared tothat in PC-3 tumors, suggesting that the efficacy was impaired byP-gp-mediated drug resistance, and these results are in very goodagreement with our in vitro cytotoxicity or apoptosis data. In contrastto the lack of efficacy of docetaxel in PC-3/TxR tumors, orallyadministered 17ya (6.7 mg/kg) demonstrated more than 100% TGI without aneffect on their body weights (FIG. 11B and Table 12). In addition, 2 outof 4 nude mice bearing PC-3/TxR tumors were tumor free on day 19 (datanot shown).

The PC-3/TxR xenograft model was further utilized to evaluate efficaciesof 17ya (in other dosing schedules) and 55. The maximal tolerated dose(body weight loss>20%) of 17ya was found to be 10 mg/kg, when orallydosed once daily for four days; or at 3.3 mg/kg twice a day (b.i.d.) forfive days (data not shown.

As shown in FIG. 11C, 3.3 mg/kg of 17ya was dosed b.i.d. for firstconsecutive four days in the first week, and the schedule was thenchanged to once daily between weeks 2 and 4. The result shows thatpartial regression was obtained during day 4-19, and the TGI was 97%,and one of the seven mice was tumor free on day 26. Higher dose (10mg/kg) with lower dosing frequency (q2d) of 17ya (FIG. 11D) elicitedpartial regression during days 13 to 29. These data suggest thatregimens with optimized doses and dosing schedules will facilitate 17yato successfully inhibit PC-3/TxR tumors. 55, was orally administered tonude mice with 10 or 30 mg/kg b.i.d., and five times a week betweenweeks 1 and 4. As shown in FIG. 11C, the inhibition profiles exhibit adose-response in PC-3/TxR tumor. The TGI value was 59% for the treatmentgroup with a lower dose (10 mg/kg). Moreover, the higher dose (30 mg/kg)started to show partial regression (>100% TGI) from day 19 to thetermination of the study (day 26). Some mice in the vehicle group lostbody weight at the endpoint, in part, due to cancer cachexia. On thecontrary, mice treated with 17ya (3.3 mg/kg) or 55 (30 mg/kg) weregaining weight (Table 12), suggesting that these optimized doses of 17yaor 55 may be well-tolerated and were preventive of cancer cachexia.

TABLE 12 Antitumor activity of compounds 17ya and 55 versusconcomitantly evaluated docetaxel in vivo. Dosing End Number Body weight(g) Tumor size (mm³) Schedule point End/Start Start End Start End TGI(%) PC-3 xenograft Vehicle_IV day 1 and 9 day 19 6/6 30 ± 2 32 ± 4 271 ±83  875 ± 292 — Docetaxel_IV_10 mpk day 1 and 9 day 19 5/5 29 ± 2 24 ± 2247 ± 49  341 ± 101 84 Docetaxel_IV_20 mpk day 1 and 9 day 19 5/5 28 ± 324 ± 3 243 ± 68  172 ± 62  >100 PC-3/TxR xenograft Vehicle_IV day 1 and9 day 19 5/5 33 ± 1 26 ± 5 171 ± 57  2061 ± 858 — Docetaxel_IV_10 mpkday 1 and 9 day 19 4/4 31 ± 2 25 ± 2 143 ± 20  1774 ± 183 14Docetaxel_IV_20 mpk day 1 and 9 day 19 4/4 30 ± 1 25 ± 4 170 ± 86   999± 905 56 17ya_PP_6.7 mpk   qd × 5/w day 19 4/4 33 ± 3 34 ± 3 172 ± 69  126 ± 100 >100 Vehicle_PO b.i.d × 5/w day 26 6/7 30 ± 2 25 ± 2 156 ±30   2591 ± 1423 — 55_PO_10 mpk b.i.d × 5/w day 26 7/7 29 ± 2 26 ± 3 143± 44  1152 ± 433 59 55_PO_30 mpk b.i.d × 5/w day 26 7/7 29 ± 3 30 ± 2134 ± 34  101 ± 19 >100 17ya_PO_3.3 mpk^(a)   qd × 5/w day 26 7/7 29 ± 230 ± 2 139 ± 44   214 ± 172 97 Vehicle_PO  q2d × 3/w day 29 5/5 24 ± 221 ± 1 299 ± 40  1521 ± 580 — 17ya_PO_10 mpk  q2d × 3/w day 29 5/5 24 ±2 28 ± 2 294 ± 156  237 ± 103 >100

Brain Penetration of 17ya and 55 in Nude Mice.

Whole brain concentrations in nude mice at 1 h and 4 h after oraladministration of 20 mg/kg 17ya or 55 were determined (Table 13). Theratios of brain to plasma concentrations were determined and compared todocetaxel in the nude mice. 55 exhibited greater brain penetration than17ya and docetaxel. 17ya only exhibited slightly greater brain/plasmaconcentration ratios than docetaxel at both 1 and 4 h. The brainconcentrations of 55 reached 14 to 19% of plasma concentrations at 1 hand 4 h, respectively, showing a 3.2-fold higher brain/plasma ratio atboth 1 h and 4 h compared to docetaxel. These data suggest that 55exhibited potentially favorable properties to treat glioma, since it hasgreater brain penetration and high potency (22 nM, Table 9) in gliomacells.

TABLE 13 Brain-Blood Barrier (BBB) studies of compounds 17ya and 55.Brain and plasma concentrations were determined in nude mice at 1 and 4h after administration of docetaxel (IP, 10 mpk), 17ya (PO, 20 mpk), and55 (PO, 20 mpk). Each value represents the mean ± SD from 3 nude mice.Docetaxel 17ya 55 Measurement 1 hr 4 hr 1 hr 4 hr 1 hr 4 hr Brain(ng/mL)  33 ± 14 20 ± 9 124 ± 108 49 ± 32 180 ± 44  73 ± 18  Plasma(ng/mL) 768 ± 92 345 ± 94 2058 ± 1252 570 ± 438 1669 ± 867 380 ± 32 Brain/plasma (%)  4.4 ± 2.0  6.0 ± 2.9 5.4 ± 1.9 8.9 ± 1.7   14 ± 7.9 19 ± 3.1

Example 18: Vascular Disrupting Activity of Compounds 17ya and 55 Method

Cells.

HUVECs (Human Umbilical Vein Endothelial Cells) were cultured and grownin EGM-2 BulletKit (Lonza, Cat No. CC-3162), which contains growthsupplements including hydrocortisone, human fibroblast growthfactor-basic with heparin (hFGF-B), vascular endothelial growth factor(VEGF), insulin-like growth factor 1 (IGF-1), ascorbic acid, heparin,fetal bovine serum, human epidermal growth factor (hEGF), and GA-1000(gentamicin and amphotericin B) in Endothelial Cell Basal Medium-2.Cells between the third and fifth passages were used for experiments.PC-3 human prostate cancer cells and T47D human breast cancer cells werecultured in RPMI-1640 medium with 5% fetal bovine serum.

Cell Growth Inhibition Studies.

Cytotoxic or antiproliferative activity of test compounds wasinvestigated in several cell lines using the sulforhodamine B (SRB)assay. Cultured cells were plated into 96-well plates and incubated inmedium containing different concentrations of the test compounds for 24h or 48 h. Cells were stained with sulphorhodamine B (SRB) solution. Theoptical density was determined at 540 nm on a microplate reader (DynexTechnologies, Chantilly, Va.). Plots of percent inhibition of cellgrowth versus drug concentration were constructed, and the concentrationthat inhibited cell growth by 50% relative to the vehicle control (IC₅₀)was determined by nonlinear least squares regression using WinNonlinsoftware (Pharsight Corporation, Cary, N.C.).

Capillary Formation and Disruption Assays.

Capillary formation assays were performed in 96-well plates by plating12,000 cells/wells of HUVECs on a Matrigel layer (BD Biosciences). Inorder to evaluate the anti-capillary action, capillaries were allowed toform over a 16 h period before the addition of test compound orvehicle-control. In addition, capillary formation inhibitory effect oftest compound was investigated by treating HUVEC cells with testcompounds before capillary formation. Images were acquired immediatelyfollowing compound addition, 5, 10, 15, and 25 h after exposure to testcompound. Capillary formation was quantified by counting the number oftubes and nodes having at least three edges.

Endothelial Monolayer Permeability Assay.

The permeability of an endothelial cell monolayer was assessed in thetranswell system. HUVECs were plated at 2×10⁶ cells per insert of 24well plates in EGM-2 medium and incubated for 72 h to reach 100%confluency. Test compounds were diluted in EGM-2 medium and added to theupper chamber of the apparatus. Following 1, 2, and 4 h of incubation,the compounds were removed and 75 μg/mL of FITC-conjugated dextran (MW40,000) was added for 5 minutes. Fluorescent measurements of the lowerchamber were taken after excitation at 485 nm and emission was measuredat 520 nm using a BioTek Synergy 4 Microplate Reader.

Result

17ya and 55 Exhibited High Antiproliferative Activity AgainstEndothelial Cells.

17ya and 55 were evaluated for cytotoxic activity against growthfactor-supplemented endothelial cells and growth factor-deprivedendothelial cell cultures. Combretastatin A-4 (CA4) and doxorubicin wereused as positive and negative control, respectively. Compound 17yaexhibited higher potency than compound 55 against actively proliferatingendothelial cells (Table 14 and FIG. 12). Both 17ya and 55 exhibitedselectivity for endothelial cells showing lower IC₅₀ values compared toone of the prostate cancer cells. CA4, 17ya and 55 were 8, 5 and 3 timesmore active against endothelial cells than against cancer cells,respectively, while doxorubicin was not specific to endothelial cells(Table 14 and FIG. 12). However no selectivity was observed betweenquiescent and active endothelial cells with these compounds (data notshown).

TABLE 14 Endothelial cell growth inhibition of 17ya and 55 (N = 3). CA4Doxorubicin 17ya 55

PC3 3.2 397.0 7.8 23.3 T47D 6.0 352.8 18.0 37.4 HUVEC 1.2 273.6 2.8 9.7Selectvity 7.6 1.4 4.6 3.1 ratio*, cancer/cells HUVEC *To obtain theselectivity ratio between cancer cells and HUVEC cells, the mean IC₅₀(nM) values of test compounds in PC3 and T47D cells were used.

17ya Disrupts the Formation of Endothelial Capillaries but does notDisrupt Preformed Capillaries.

The activity of 17ya was investigated on endothelial cells engaged incapillary tube formation in vitro. Endothelial cells were placed on aMatrigel matrix and the formation and construction of capillary tubes inthe presence or absence of compounds were observed (CA4, doxorubicin,and 17ya).

To avoid confusion between early stage of tube formation and disruptionof tube construction, HUVEC cells on matrix in the presence of drugtreatment were incubated for 15 h. Then disruption of capillary wasdetermined by counting the number of tubes and nodes in each treatmentgroup. On the other hand, to evaluate the effect of test compound inpreformed capillaries, HUVEC cells on matrix were allowed to formcapillary tube for 16 h and the capillaries were treated with testcompounds.

As a result, the number of tubes and nodes was gradually decreased overtime due to deficiency or consumption of nutrient by HUVEC cells (FIG.13). This trend was observed in every drug treatment group (FIG. 13). Inorder to examine the difference between untreated and pretreatedcapillaries 15 h incubation groups were compared (FIG. 13).

Endothelial cells that were exposed to various concentrations of 17ya (0to 50 μM) plated on Matrigel matrix resulted in inhibition of tubeformation in a dose dependent manner. 17ya with approximate IC₅₀ valueof 5 nM in cell growth inhibition studies inhibited more than 50% oftube formation compared to vehicle-control (FIG. 14). 17ya at 10 nMcompletely inhibited the tube formation (FIG. 14). However, in thepreformed capillaries, the 10 nM 17ya treatment group did not disruptthe capillary structure by 15 h (FIG. 13). These results suggest that17ya inhibits the formation of endothelial capillaries significantly butis less effective to disrupt preformed capillaries. Similar result wasobserved in CA4 treatment group (FIG. 14). However, doxorubicin did notaffect the capillary construction at toxic concentration.

17ya and 55 Increased the Permeability of Endothelial Cell Monolayers.

Antitubulin agents could modify the integrity of endothelial cell layerslining blood vessels by targeting cytoskeleton of the endothelial cells.Thus, the vascular disruption effect of antitubulin agent is known toincrease the permeability of blood vessel and thus could lead to proteinleakage and high blood viscosity. This could result in reduction ofblood flow, causing subsequent tumor death from hypoxia and nutrientdeprivation.

The effect of 17ya and 55 was evaluated on vascular permeability usingin vitro study using transwell system with confluent HUVEC monolayers.The change in permeability by test compound was measured by the leakageof dextran (MW 40,000) after 1, 2, and 4 h of drug treatment. CA4 wasused as a positive control. CA4, 17ya, and 55 resulted in increasedpermeability and the effect was more pronounced at 1 h incubation (datawas not shown). 17ya showed a potency similar to CA4 (FIG. 15).Doxorubicin did not induce any change in the permeability of endothelialcell monolayer (FIG. 15).

Example 19: In Vivo Efficacy of 17ya in Leukemia (HL60) Xenograft (FIG.16)

HL60 cells (10×10⁷ per mL) were prepared in RPMI1640 growth mediacontaining 10% FBS, and mixed with Matrigel (BD Biosciences, San Jose,Calif.) at 1:1 ratio. Tumors were established by injecting 100 μL of themixture (5×10⁶ cells per animal) subcutaneously into the flank of6-8-week-old male athymic nude mice. Length and width of tumors weremeasured and the tumor volume (mm³) was calculated by the formula,π/6×L×W², where length (L) and width (W) were determined in mm. When thetumor volumes reached 200 mm³ approximately, the animals bearing HL60tumors were treated with vehicle [Tween80/DMSO/H₂O (2/2/6)], or 17ya (20mg/kg) orally. The dosing schedule was once a week for two weeks.Vincristine (1 mg/mL) was administrated via intraperitoneal injectiononce a week.

Results

Human promyelocytic leukemia cells, HL60 cells were inoculated in nudemice and the tumor volumes were allowed to reach about 200 mm³.Vincristine (1 mg/kg), which is in clinic for hematological cancersincluding leukemia, was used to evaluate the response of this in vivomodel against a positive control drug. The tumor volumes (mm³) wereplotted against time and are the means±SD from four to five animals.HL60 tumor was found to be fast-growing and the volume reached 2000-3000mm³ within two weeks. Though 1 mg/kg intraperitoneal injection ofvincristine exhibited very potent tumor growth inhibitory effect (FIG.16) and the tumor growth inhibition (TGI) was 84%. Orally administered17ya (20 mg/kg) showed 40% tumor growth inhibition. The size of HL60tumors was maintained up to 5 days after 17ya treatment without dramaticincrease but during the next 2 days tumor sizes increased significantly(60-100%). It suggests that a more frequent dosing schedule couldenhance the tumor growth inhibitory effect of 17ya.

Example 20: Synthesis of a Derivative of Compound 31

Compound 31a was synthesized by the addition of sodium hydride (60%dispersion in mineral oil, 20 mg, 0.5 mmol) to 31 and stirred for 20min. Methyl iodide (70 mg, 0.5 mmol) was added, and the reaction mixturewas stirred 1 h. After dilution by 20 ml of saturated NaHCO₃ solution(aqueous), the reaction mixture was extracted by ethyl acetate (60 ml).The organic layer was dried over magnesium sulfate and concentrated. Theresidue was recrystallized from water and methanol to give a white solidof 31a.(2-(1-Methyl-1H-indol-5-yl)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(Compound 31a): Yield: 75% ¹H NMR (300 MHz, CDCl₃) δ 8.28 (br, 1H), 8.21(br, 1H), 7.95-7.91 (dd, 1H), 7.83 (s, 2H), 7.38 (d, 1H), 7.25 (t, 1H),6.67 (t, br, 1H), 3.98 (s, 9H), 3.85 (s, 3H). MS (ESI) m/z 431.3.

Example 21: In Vitro and In Vivo Pharmacology of Compounds 17ya, 31, and31a Materials and Methods Cell Culture and Cytotoxicity Assay ofProstate, Lung, Colon, Breast, Uterine and Ovarian Cancers.

All cancer cell lines (PC-3-prostate cancer, PC-3/TXR prostatecancer-multidrug resistant (MDR), A549-lung cancer, C26-colon cancer,MCF7-breast cancer, MES-SA-uterine cancer and MES-SA/DX5-uterinecancer-MDR) were obtained from ATCC (American Type Culture Collection,Manassas, Va., USA) unless otherwise specified. Both ovarian cell lines(OVCAR8-ovarian cancer and NCI/ADR-RES-ovarian cancer-MDR) were obtainedfrom National Cancer Institutes (NCI). Human PC-3_TxR, was resistant topaclitaxel and used as a MDR model compared with PC-3. Human MES-SA/DX5was resistant to doxorubicin and used as a MDR model compared withMES-SA. Human NCI/ADR-RES was resistant to Adriamycin and used as a MDRmodel compared with OVCAR8. Cell culture supplies were purchased fromCellgro Mediatech (Herndon, Va., USA). All cell lines were used to testthe antiproliferative activity of compounds 17ya(2-(1H-indol-3-yl)imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone, 31(2-(1H-indol-5-yl)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone, and31a(2-(1-methyl-1H-indol-5-yl)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanoneby sulforhodamine B (SRB) assay. All cancer cell lines were maintainedin RPMI 1640 media with 2 mM glutamine and 10% fetal bovine serum (FBS).

Metabolic Incubations.

Metabolic stability studies were conducted for compound 17ya and 31 byincubating 0.5 μM of test compounds in a total reaction volume of 1 mLcontaining 1 mg/mL microsomal protein in reaction buffer [0.2 M ofphosphate buffer solution (pH 7.4), 1.3 mM NADP⁺, 3.3 mMglucose-6-phosphate, and 0.4 U/mL glucose-6-phosphate dehydrogenase] at37° C. in a shaking water bath. The NADPH regenerating system (solutionA and B) was obtained from BD Biosciences (Bedford, Mass.). Forglucuronidation studies, 2 mM UDP-glucuronic acid (Sigma, St. Louis,Mo.) cofactor in deionized water was incubated with 8 mM MgCl₂, 25 μg ofalamethicin (Sigma, St. Louis, Mo.) in deionized water, and NADPHregenerating solutions (BD Biosciences, Bedford, Mass.) as describedpreviously. The total DMSO concentration in the reaction solution wasapproximately 0.5% (v/v). Aliquots (100 μL) from the reaction mixturesused to determine metabolic stability were sampled at 5, 10, 30, 60, 90and 120 min. Acetonitrile (150 μL) containing 200 nM of the internalstandard was added to quench the reaction and to precipitate theproteins. Samples were then centrifuged at 4,000 g for 30 min at RT, andthe supernatant was analyzed directly by LC-MS/MS.

Analytical Method.

Sample solution (10 μL) was injected into an Agilent series HPLC system(Agilent 1100 Series Agilent 1100 Chemstation, Agilent Technology Co,Ltd). All analytes were separated on a narrow-bore C18 column (AlltechAlltima HP, 2.1×100 mm, 3 μm, Fisher, Fair Lawn, N.J.). Two gradientmodes were used. For metabolic stability studies, gradient mode was usedto achieve the separation of analytes using mixtures of mobile phase A[ACN/H₂O (5%/95%, v/v) containing 0.1% formic acid] and mobile phase B[ACN/H₂O (95%/5%, v/v) containing 0.1% formic acid] at a flow rate of300 μL/min. Mobile phase A was used at 10% from 0 to 1 min followed by alinearly programmed gradient to 100% of mobile phase B within 4 min,100% of mobile phase B was maintained for 0.5 min before a quick ramp to10% mobile phase A. Mobile phase A was continued for another 10 mintowards the end of analysis.

A triple-quadruple mass spectrometer, API Qtrap 4000™ (AppliedBiosystems/MDS SCIEX, Concord, Ontario, Canada), operating with aTurbolonSpray source was used. The spraying needle voltage was set at 5kV for positive mode. Curtain gas was set at 10; Gas 1 and gas 2 wereset 50. Collision-Assisted-Dissociation (CAD) gas at medium and thesource heater probe temperature at 500° C. [Multiple reaction monitoring(MRM) mode, scanning m/z 378→210 (17ya), m/z 373→205 (12fa), m/z 410→242(55) and m/z 309→171 (internal standard), was used to obtain the mostsensitive signals. Data acquisition and quantitative processing wereaccomplished using Analyst™ software, Ver. 1.4.1 (Applied Biosystems).

Aqueous Solubility.

The solubility of drugs was determined by Multiscreen Solubility FilterPlate (Millipore Corporate, Billerica, Mass.) coupled with LC-MS/MS.Briefly, 198 μL of phosphate buffered saline (PBS) buffer (pH 7.4) wasloaded into 96-well plate, and 2 μL of 10 mM test compounds (in DMSO)was dispensed and mixed with gentle shaking (200-300 rpm) for 1.5 hoursat RT (N=3). The plate was centrifuged at 800 g for 10 min, and thefiltrate was used to determine its concentration and solubility of testcompound by LC-MS/MS as described previously.

Pharmacokinetic Study.

Female Sprague-Dawley rats (n=3; 254±4 g) were purchased from HarlanInc. (Indianapolis, Ind.). Rat thoracic jugular vein catheters werepurchased from Braintree Scientific Inc. (Braintree, Mass.). On arrivalat the animal facility, the animals were acclimated for 3 days in atemperature-controlled room (20-22° C.) with a 12 h light/dark cyclebefore any treatment. Compounds 17ya and 31 were administered i.v. intothe thoracic jugular vein at a dose of 5 mg/kg (in DMSO/PEG300, 1/9). Anequal volume of heparinized saline was injected to replace the removedblood, and blood samples (250 μL) were collected via the jugular veincatheter at 10, 20, 30 min, and 1, 2, 4, 8, 12, 24 h. Rats were given(p.o.) by oral gavage at 10 mg/kg (in Tween80/DMSO/H₂O, 2/2/6) of eachtest compound to evaluate their oral bioavailability. All blood samples(250 μL) after oral administration were collected via the jugular veincatheter at 30, 60, 90 min, 120 min, 150 min, 180 min, 210 min, 240 min,and 8, 12, 24 h. Heparinized syringes and vials were prepared prior toblood collection. Plasma samples were prepared by centrifuging the bloodsamples at 8,000 g for 5 min. All plasma samples were stored immediatelyat −80° C. until analyzed.

Analytes were extracted from 100 μL of plasma with 200 μL ofacetonitrile containing 200 nM the internal standard. The samples werethoroughly mixed, centrifuged, and the organic extract was transferredto autosampler for LC-MS/MS analysis.

Results

Compounds 17ya, 31 and 31a Exhibit Broad Cytotoxicity in Cancer Cells,Including Multidrug-Resistant Cancer Cells.

The ability of 17ya, 31 and 31a to inhibit the growth of cancer celllines was evaluated using an SRB assay (Table 15). All three compoundsinhibited the growth of several human cancer cell lines, includingprostate, lung, colon, breast, uterine, doxorubicin-resistant uterine,ovarian and adriamycin-resistant ovarian cancer cell lines, with IC₅₀values in the low nanomolar range.

Doxorubicin-resistant MES-SA (MES-SA/DX5) cell line andadriamycin-resistant OVCAR8 (NCI/ADR-RES) cell line that express highlevels of mdr-1 mRNA resulting in the over-expression of P-glycoprotein(P-gp), were used to study the effect of 17ya, 31 and 31a on multi-drugresistant cell lines and to compare results against parent lines, MES-SAcell line and OVCAR8 cell line, respectively. The IC₅₀ values ofdocetaxel (DTX) were 0.1 nM and 26 nM in MES-SA and MES-SA/DX5 cells,respectively, and 0.4 nM and 2471 nM in OVCAR8 and NCI/ADR-RES cells,respectively, demonstrating a significant reduction of effectiveness indrug-resistant cancer cells. Docetaxel exhibited relative resistance of4260-fold (resistance factor; MES-SA vs. MES-SA/Dx5) and 6042.5-fold(resistance factor; OVCAR8 vs. NCI/ADR-RES), respectively. In contrast,compounds 17ya, 31 and 31a were equipotent against parent MES-SA orOVCAR8 cell lines and MES-SA/DX5 or NCI/ADR-RES multidrug resistant celllines, respectively. Uniformly, 17ya, 31 and 31a demonstrated at leastan order of magniture (i.e., 10-fold) increased potency compared to DTXin multidrug resistant cells lines. (Table 15) These data indicate that17ya, 31 and 31a circumvent P-gp-mediated drug resistance.

TABLE 15 Cytotoxicity data of 17ya, 31 and 31a IC₅₀ (nM) in the SRB DTX17ya 31 31a

PC3 Prostate 1-5 7-10 7 5 A549 Lung 0.2 22 9 21 C26 Colon 4 7 5 16 MCF7Breast 0.1 13 11 22 MES-SA Uterine 0.1 9 6 18 MES-SA/ 426 14 8 18 DX5OVCAR8 Ovary 0.4 12 11 16 NCI/ADR- 2471 19 5 14 RES IC₅₀ values areexpressed in nM and were determined after 96 h treatment (N = 3).Docetaxel was used as a positive control.

As shown in FIG. 18, 17ya had a half-life that was much longer than 31or 31a as seen by the larger area under the curve in in vitro phase Ireactions with human liver microsomes. This suggested that 17ya wasstable in phase I metabolic processes. These data suggested that allthree compounds showed acceptable stability in human liver microsomes,and 17ya is more stable than 31 or 31a.

Compounds 17ya, 31 and 31a Exhibited Favorable Drug-Like Properties.

Drug-like properties, such as metabolic stability, bioavailability (AUC;min*μg/mL), clearance (Cl; mL/min/kg) and steady-state volume ofdistribution (Vss; L/kg) were examined for 17ya, 31 and 31a (metabolicstability only for 31a) (FIGS. 18, 19A, 19B and 19C; Table 16). 17yaexhibited superior metabolic stability compared with 31 and 31a (FIG.18). As seen in the concentration time plots, 17ya also demonstratedsuperior stability in vivo when injected (FIGS. 19A, 19B) and doseorally (FIG. 19C) compared to 31 (Table 16).

TABLE 16 Pharmacokinetic properties of compounds 17ya and 31. 31 17ya 10min-48 h 20 min-48 h AUC 553 828 3210 210 249 (min * μg/mL) CI 10 6 1 2318 (mL/min/kg) Vss (L/kg) 1.8 0.8 0.03 12 5

Example 22: Xenograft Efficacy Studies Using Compound 17ya to TreatMulti-Drug Resistant (MDR) and Non-MDR Tumors

Materials and Methods

Cell culture of prostate, lung, colon, breast, uterine and ovariancancer cell lines was as above in Example 21. Additionally, MCF7(breast) cells were obtained from ATCC (American Type CultureCollection, Manassas, Va., USA). Cell lines were used to developxenografts in order to test in vivo the anti-tumor growth activity ofcompound 17ya(2-(1H-indol-3-yl)imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone.

Xenograft Studies.

PC-3, PC-3_TxR, MES-SA/DX5, OVCAR8, NCI/ADR-RES, A549, C26 and MCF7cells (10×10⁷ per mL) were prepared in RPMI1640 growth media containing10% FBS, and mixed with Matrigel (BD Biosciences, San Jose, Calif.) at1:1 ratio. Tumors were established by injecting 100 μL of the mixture(5×10⁶ cells per animal) subcutaneously (s.c.) into the flank of6-8-week-old male athymic nude mice. Length and width of tumors weremeasured and the tumor volume (mm³) was calculated by the formula,π/6×L×W², where length (L) and width (W) were determined in mm. When thetumor volumes reached 300 mm³, the animals bearing tumors were treatedwith vehicle [Tween80/DMSO/H₂O (2/2/6)] or docetaxel (DTX) (10 mg/kgonce per week) or 17ya intravenously or orally. The dosing schedule for17ya included trials at 7 mg/kg once per week; 10 mg/kg once per week;15 mg/kg once per week; 15 mg/kg twice per week; 15 mg/kg three timesper week; and 20 mg/kg once per week.

Results

Compound 17ya Inhibits Tumor Growth in Nude Mice Bearing Prostate,Paclitaxel Resistant Prostate (PC3/TXR), Ovarian, Adriamycin-ResistantOvarian (NCI/ADR-RES), Doxorubicin-Resistant Uterine (MES-SA/DX5), Lungand Colon Cancer Xenografts.

PC3, paclitaxel-resistant prostate cancer (PC-3/TxR),doxorubicin-resistant uterine cancer (MES-SA/DX5), ovarian cancer,adriamycin-resistant ovarian cancer (NCI/ADR-RES), lung cancer and coloncancer cells were inoculated in nude mice and the tumor volumes wereallowed to reach about 150-300 mm³. Docetaxel (10 mg/kg), which is inthe clinic for prostate cancer, was used as a positive control toevaluate its effectiveness in models of parental and P-gp-mediated drugresistant xenografts in vivo.

The results of these studies are summarized in Table 17 below.

TABLE 17 Dose (mg/kg) TGI (%) DTX PC3 Prostate IV 10 1/wk 84 PC3/TXRProstate (MDR) IV 10 1/wk 14 MES-SA/DX5 Uterine (MDR) IV 10 1/wk 47OVCAR8 Ovary IV 10 1/wk 22 A549 Lung IV 10 1/wk 44 C26 Colon IV 10 1/wk35 MCF7 Breast IV 10 1/wk <5 GTx230 PC3 Prostate IV 10 1/wk 72 PC3Prostate PO 15 2/wk 83 PC3/TXR Prostate (MDR) PO 20 1/wk >100 OVCAR8Ovary PO 20 1/wk 8 OVCAR8 Ovary PO 15 2/wk 63 NCI/ADR-RES Ovary (MDR) PO15 1/wk 99.6 MES-SA/DX5 Uterine (MDR) PO 20 1/wk 60 MES-SA/DX5 Uterine(MDR) PO 15 2/wk 72 A549 Lung PO 20 1/wk 62 C26 Colon PO 20 1/wk 61

Non-MDR Xenografts:

Ten (10) mg/kg intravenously administered docetaxel exhibited tumorgrowth inhibition (TGI) in xenografts: PC-3 (prostate) xenografts of84%, and to a lesser extent in OVCAR8 (ovarian; TGI of 22%, A549 (lung;TGI of 44%) and C26 (colon; TGI of 35%). DTX administration exhibitedless than 5% TGI in breast cancer xenografts. In comparison, Table 17shows that intravenous or oral administration of 17ya (10/15/20 mg/kg)exhibited reduced tumor growth over a wide range of tumor typesincluding xenografts of: PC3 (prostate; TGI of 72% and 83%), OVCAR8(ovarian; TGI of 63%), A549 (lung; TGI of 62%) and C26 (colon; TGI of61%). Thus, compound 17ya was effective in a range of tumor types andparticularly showed significantly greater TGI than DTX in ovarian, lung,and colon cancers.

17ya Exhibited Greater Effectiveness than DTX in Drug-Resistant ProstateTumors.

Comparison of prostate and prostate-MDR tumor growth showed thatadministration of DTX (10 mg/kg) resulted in a significantly decreasedTGI effect from 84% TGI in PC-3 tumors compared with only 14% TGI inPC-3/TxR tumors (Table 17). Thus, the effectiveness of docetaxel inPC-3/TxR tumors was dramatically decreased when compared to that in PC-3tumors, suggesting that the efficacy of DTX was impaired byP-gp-mediated drug resistance. In contrast to the lack of efficacy ofdocetaxel in PC-3/TxR tumors, orally administered 17ya (20 mg/kg)demonstrated more than 100% TGI in PC3/TXr xenografts.

In addition, 17ya showed effective tumor growth inhibition (TGI) inMDR-xenografts from NCI/ADR-RES (adriamycin resistant ovarian cancercells) of 99.6% TGI, and for MES-SA/DX5 (doxorubicin resistant uterinecancer cells) the efficacy was 60% and 72% TGI. (Table 17).

Effectiveness of 17ya in PC3 and PC3/TXR Xenografts (Prostate Cancer andPaclitaxel-Resistant Prostate Cancer, Respectively).

Intravenously administered 17ya at 7 mg/kg once per week or orallyadministered 17ya at 15 mg/kg once per week in mice bearing PC3xenografts demonstrated dose responsive reduction (7 mg/kg) andessentially no growth (15 mg/kg) in PC3 tumors (FIG. 20A). The efficacyof 17ya to inhibit tumor growth did not effect body weights during thissame time period (FIG. 20B).

Similarly, orally administered 17ya, 15 mg/kg once per week, exhibiteddose responsive inhibition of PC3/TXR tumor growth (FIG. 20C) in theabsence of body weight changes during the same time period (FIG. 20D).

Effectiveness of 17ya in NCI/ADR-RES Xenografts (Adriamycin-ResistantOvarian Cancer).

Orally administered 17ya at 15 mg/kg once per week or three-times perweek in mice bearing NCI/ADR-RES xenografts demonstrated dose responsiveinhibition of tumor growth and reduction of tumor size (FIG. 21A). Theefficacy of 17ya to inhibit tumor growth did not effect body weightsduring this same time period (FIG. 21B).

Effectiveness of 17ya in MES-SA/DX5 Xenografts (Doxorubicin-ResistantUterine Cancer)

Orally administered 17ya at either 15 mg/kg twice per week or 20 mg/kgonce per week, in mice bearing MES-SA/DX5 xenografts demonstrated doseresponsive inhibition of tumor growth in comparison with vehicle alone(FIG. 22B). The efficacy of 17ya to inhibit tumor growth did not affectbody weights during this same time period (FIG. 22A). Using the data forFIG. 22B, comparison of the different 17ya dosages with intravenouslyadministered DTX at 10 mg/kg once a week showed 17ya at 15 mg/kg twiceper week to be the most effective dosage for tumor growth inhibition(72%). 17ya at 20 mg/kg once per week showed 60% tumor growthinhibition, while DTX showed only 47% tumor growth inhibition.

Dosage Regime of 17ya Effects Tumor Growth Inhibition in OVCAR8Xenografts (Ovarian Cancer)

The effectiveness of 17ya to reduce tumor size of ovarian xenographs wasmarkedly increased with a twice weekly dosage regime. While orallyadministered 17ya at 20 mg/kg once per week in mice bearing OVCAR8xenografts showed minimal reduction of tumor size (8%), orallyadministered 17ya at 15 mg/kg twice per week, exhibited significanttumor size reduction (63%) compared with vehicle alone (FIGS. 23A and23B). The effectiveness of intravenously administered DTX at 10 mg/kgonce per week was significantly less (22%; FIG. 23A) than thetwice-weekly dose regime of 17ya (63%). The twice-weekly 17ya doseregime showed minimal weight increase over the same time period comparedwith vehicle alone (FIG. 23C).

All of the features described herein (including any accompanying claims,abstract and drawings), and/or all of the steps of any method or processso disclosed, may be combined with any of the above aspects in anycombination, except combinations where at least some of such featuresand/or steps are mutually exclusive. Although preferred embodiments havebeen depicted and described in detail herein, it will be apparent tothose skilled in the relevant art that various modifications, additions,substitutions, and the like can be made without departing from thespirit of the invention and these are therefore considered to be withinthe scope of the invention as defined in the claims which follow.

What is claimed:
 1. A compound selected from the following group:(2-(1-H-indol-1-yl)imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;(2-(1-H-indol-2-yl)imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;(2-(1-H-indol-4-yl)imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;(2-(1-H-indol-5-yl)imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;(2-(1-H-indol-6-yl)imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone; and(2-(1-H-indol-7-yl)imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone, or apharmaceutically acceptable salt thereof, a hydrate thereof, or acombination thereof.
 2. A pharmaceutical composition comprising acompound according to claim 1 and a pharmaceutically acceptable carrier.3. A compound according to claim 1 for use as a medicament.
 4. Use of acompound of claim 1, for the preparation of a medicament for treatingprostate cancer, breast cancer, ovarian cancer, skin cancer, lungcancer, colon cancer, leukemia, renal cancer or CNS cancer, or acombination thereof.
 5. The use according to claim 4, wherein themedicament is administered systemically.
 6. The use according to claim4, wherein the medicament is administered orally, topically,transdermally, parenterally, subcutaneously, intravenously,intramuscularly, intraperitoneally, by intranasal instillation, byintracavitary or intravesical instillation, intraocularly,intraarterially, intralesionally, or by application to mucous membranes.7. The use according to claim 4, wherein the medicament is administereddirectly to a site where cancer cells are present.
 8. The use accordingto claim 4, wherein the medicament is administered at a dosage rate ofabout 0.01 to about 100 mg of the compound per kg·body weight.
 9. Theuse according to claim 4, wherein the medicament is administeredperiodically.
 10. The use according to claim 4, wherein the medicamentis administered in combination with another cancer therapy.
 11. Thecompound of claim 1 or a pharmaceutical composition according to claim2, for use in treating a subject suffering from cancer, wherein saidcancer is selected from the group consisting of prostate cancer, breastcancer, ovarian cancer, skin cancer, lung cancer, colon cancer,leukemia, renal cancer, CNS cancer, or any combination thereof.
 12. Thecompound for use according to claim 11, wherein the compound isadministered orally, topically, transdermally, parenterally,subcutaneously, intravenously, intramuscularly, intraperitoneally, byintranasal instillation, by intracavitary or intravesical instillation,intraocularly, intraarterially, intralesionally, or by application tomucous membranes.
 13. The compound for use according to claim 11,wherein the compound is administered at a dosage rate of about 0.01 toabout 100 mg/kg·body weight.
 14. The compound for use according to claim11, wherein the compound is administered systemically.
 15. The compoundfor use according to claim 11, wherein the compound is administeredperiodically.
 16. The compound for use according to claim 11, whereinthe compound is administered in combination with another cancer therapy.